Novel shogaol compound and tyrosinase activity inhibitor comprising the compound

ABSTRACT

The compound represented by the following formula (1):  
                 
wherein A, B, R1, R2, R3 and Z are as defined in the specification is analogous to shogaol and gingerol useful in the fields of foods, medicines, quasi-drugs, cosmetics, etc., and more highly active in tyrosinase activity inhibition, etc. than shogaol and gingerol.

TECHNICAL FIELD

The present invention relates to a novel compound having a chemicalstructure similar to shogaol and gingerol, which are useful in thefields of foods, medicines, quasi-drugs, cosmetics, etc., and to anintermediate for producing the same. In addition; it relates to atyrosinase activity inhibitor, hyaluronic acid-degrading enzymeinhibitor, an antioxidant, or the like comprising the novel compound asan active ingredient.

BACKGROUND ART

Pigmentation due to spots, freckles, and the like emerges throughformation of melanin pigment in epidermal chromocytes and abnormaldeposition thereof in epidermis caused by ultraviolet exposure and thelike. Melanin pigment is synthesized by metabolism of L-tyrosine as oneof amino acids into L-dopa and then L-dopaquinone by the action oftyrosinase as an oxidative enzyme thereof and subsequent variouspathways (cf. e.g., Fine Chemicals, issue on Mar. 15, 1999, “SpecialTopic: Bihakuzai no Kaihatsu to Seihin Tenkai (Development and Productsof Whitening Agents)”; and Fragrance Journal, issue on September 1997,“Special Topic: Saikin no Bihakuzai no Kenkyu Kaihatsu Doko (RecentTrend of Researches and Development of Whitening Agent)”). Thus, inorder to prevent pigmentation due to spots, freckles, and the like, itis important to inhibit activity of tyrosinase which plays an importantrole for melanin pigment synthesis.

Hitherto, for preventing and improving spots, freckles, and the like,there have been used pharmaceutical agents such as placenta extracts,vitamin C, vitamin C derivatives, kojic acid, and arbutin. However,these agents have resulted in no sufficient effect. Moreover, in Europeand the United States, hydroquinone has been used for the purpose ofdecoloration of dye freckles but use thereof is limited because ofproblems in safety. Furthermore, recently, a possibility ofcarcinogenicity is also pointed out for kojic acid and thus becomes aproblem.

On the other hand, shogaol and gingerol are components of gingerextracts and they are known to have, for example, a bloodcirdulation-facilitating effect (JP-A-6-183959), a body odor-preventingeffect (U.S. Pat. No. 6,264,928), an antioxidation effect (H. Kikuzaki,N. Nakatani, “Antioxidant Effects of Some Ginger Constituents”, J. FoodSci., Vol. 58, No. 6, 1407-1410 (1993)), a moisturizing effect(supervising editor: Masato Suzuki, “Atarashii Keshohin Kinousozai(Novel Cosmetic Functional materials) 300, first volume”, pp. 311-312,CMC Publishing, 2002), and the like effects. Moreover, metabolic routesof shogaol and gingerol have been also researched and structures ofmetabolites thereof have been reported (H. Takahashi and other threeauthors, Phytochemistry, Vol. 34, 1497-1500 (1993) and S. S. Lee, Arch.Pharm. Res., Vol. 18, 136-137 (1995)).

The present inventors had investigated methods capable of massproduction of shogaol and they developed an industrial productionprocess of a specific shogaol as a target. Thus, they applied a patentapplication (Japanese Patent Application No. 2003-327574) on thespecific shogaol and the process for producing the same, andsimultaneously, they reported that shogaol has a property of inhibitingactivity of tyrosinase. However, since the shogaol obtained by theproduction process is insufficient in water solubility, there is a casethat it is difficult to apply to human and hence it is desired todevelop a compound which is more soluble in water.

DISCLOSURE OF THE INVENTION

It is an object of the invention to provide a compound, which is thesame class as shogaol and gingerol useful in the fields of foods,medicines, quasi-drugs, cosmetics, etc. and which is more highly activein the inhibition of tyrosinase activity or the like than shogaol andgingerol.

As a result of extensive studies for solving the above problems, thepresent inventors have found a novel compound having a basic structurethe same as that of shogaol and gingerol and having properties the sameas those of known shogaol and gingerol and also they have found that thecompound satisfactory acts as a tyrosinase activity inhibitor or thelike. Thus, they have accomplished the invention.

The invention is a compound represented by the following formula (1):

wherein R¹ is a hydrogen atom, a lower alkyl group, or a protectivegroup of a phenolic hydroxyl group, R² is a hydrogen atom or aprotective group of a phenolic hydroxyl group, A is an alkylene grouphaving 1 to 4 carbon atoms, B is an alkylene group having 1 to 12 carbonatoms, R³ is —COOR⁴ (wherein R⁴ is a protective group of a carboxylgroup), a carboxyl group, or —CH₂OH, a n d Z is —CO—CH═CH—,—CHOH—CH═CH—, —CHOH-1,2-epoxy-, —CO—CH₂CH₂—, —CHOH—CH₂CH₂—,—CO—CH₂CHOH—, —CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—, —CHOH—CH₂CHOR⁵— a ketalderivative of —CO—CH═CH—, or a ketal derivative of —CO—CH₂CH₂— and R⁵ isa lower alkyl group when R³ is a —COOR⁴ group, Z is —CO—CH═CH—,—CHOH—CH═CH—, —CHOH-1,2-epoxy-, —CHOH—CH₂CH₂—, —CHOH—CH₂CHOH—,—CO—CH₂CHOR⁵—, —CHOH—CH₂CHOR⁵—, a ketal derivative of —CO—CH═CH—, or aketal derivative of —CO—CH₂CH₂— and R⁵ is a lower alkyl group when R³ isa carboxyl group, or Z is —CHOH—CH═CH—, —CHOH-1,2-epoxy-,—CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—CHOH—CH₂CHOR⁵—, a ketal derivative of—CO—CH═CH—, or a ketal derivative of —CO—CH₂CH₂— and R⁵ is a lower alkylgroup when R³ is a —CH₂OH.

The lower alkyl group in the formula (1) has 1 to 4 carbon atoms and ispreferably a methyl group. Moreover, —CHOH-1,2-epoxy- in the formula (1)is a group represented by the following formula (3):

The ketal derivative in the formula (1) is a non-cyclic ketal or acyclic ketal, preferably a cyclic ketal. As the cyclic ketal, there maybe mentioned those obtained from ethylene glycol, 1,3-propanediol, or2,2-dimethyl-1,3-propanediol with a carbonyl group.

The invention is a tyrosinase inhibitor comprising a compoundrepresented by the above formula (1), a hyaluronic acid-degrading enzymeinhibitor comprising the compound represented by the formula (1), and anantioxidant comprising the compound represented by the formula (1).

Moreover, the invention is a tyrosinase inhibitor, a hyaluronicacid-degrading enzyme inhibitor, and/or an antioxidant comprising thecompound represented by the following formula (2):

wherein, R⁶ is a hydrogen atom, a lower alkyl group, or a protectivegroup of a phenolic hydroxyl group, A is an alkylene group having 1 to 4carbon atoms, B is an alkylene group having 1 to 12 carbon atoms, R⁷ is—COOR⁸ (wherein R⁸ is a protective group of a carboxyl group), acarboxyl group, or —CH₂OH, Z is —CO—CH═CH—, —CHOH—CH═CH—,—CHOH-1,2-epoxy-, —CO—CH₂CH₂—, —CHOH—CH₂CH₂—, —CO—CH₂CHOH—,—CHOH—CH₂CHOH—, —CO—CH₂CHOR⁹—, —CHOH—CH₂CHOR⁹—, a ketal derivative of—CO—CH═CH—, or a ketal derivative of —CO—CH₂CH₂—, and R⁹ is a loweralkyl group.

BEST MODE FOR CARRYING OUT THE INVENTION

The following will explain the present invention in more detail.

With Regard to the Compounds Represented by the General Formula (1)

In the formula (1), R¹ is a hydrogen atom, a lower alkyl group, or aprotective group of a phenolic hydroxyl group. R² is a hydrogen atom ora protective group of a phenolic hydroxyl group. As the protective groupof a phenolic hydroxyl group for R¹ and R², easy introduction andremoval of the protective group is preferable and there may beexemplified silyl-type protective groups, acyl-type protective groups,benzyl-type protective groups, ether-type protective groups, and thelike. Specifically, a t-butyldimethylsilyl group, a propionyl group, abutyroyl group, an isobutyroyl group, a pivaloyl group, a benzoyl group,a toluoyl group, a benzyl group, a tetrahydropyranyl group, and amethoxymethyl group are suitable.

In the formula (1), A is an alkylene group having 1 to 4 carbon atoms,preferably an ethylene group or a butylene group, and more preferably anethylene group.

In the formula (1), B is an alkylene group having 1 to 12 carbon atoms,preferably an alkylene group having 1 to 9 carbon atoms, and morepreferably an alkylene group having 2 to 6 carbon atoms.

In the formula (1), R³ is —COOR⁴ (wherein R⁴ is a protective group of acarboxyl group), a carboxyl group, or —CH₂OH. As the protective group ofa carboxyl group, a methyl group, an ethyl group, a propyl group, abutyl group, and a benzyl group are suitable. More preferable is amethyl group or an ethyl group.

In the formula (1), Z is —CO—CH═CH—, —CHOH—CH═CH—, —CHOH-1,2-epoxy-,—CO—CH₂CH₂—, —CHOH—CH₂CH₂—, —CO—CH₂CHOH—, —CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—,—CHOH—CH₂CHOR⁵—, a ketal derivative of —CO—CH═CH—, or a ketal derivativeof —CO—CH₂CH₂— and R⁵ is a lower alkyl group when R³ is a —COOR⁴ group.Moreover, in the formula (1), Z is —CO—CH═CH—, —CHOH—CH═CH—,—CHOH-1,2-epoxy-, —CHOH—CH₂CH₂—, —CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—,—CHOH—CH₂CHOR⁵—, a ketal derivative of —CO—CH═CH—, or a ketal derivativeof —CO—CH₂CH₂— and R⁵ is a lower alkyl group when R³ is a carboxylgroup. Furthermore, in the formula (1), Z is —CHOH—CH═CH—,—CHOH-1,2-epoxy-, —CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—, —CHOH—CH₂CHOR⁵—, aketal derivative of —CO—CH═CH—, or a ketal derivative of —CO—CH₂CH₂— andR⁵ is a lower alkyl group when R³ is a —CH₂OH.

With Regard to the Compounds Represented by the General Formula (2)

In the formula (2), R⁶ is a hydrogen atom, a lower alkyl group, or aprotective group of a phenolic hydroxyl group. As the protective groupof a phenolic hydroxyl group for R⁶, easy introduction and removal ofthe protective group is preferable and there may be exemplifiedsilyl-type protective groups, acyl-type protective groups, benzyl-typeprotective groups, ether-type protective groups, and the like.Specifically, a t-butyldimethylsilyl group, a propionyl group, abutyroyl group, an isobutyroyl group, a pivaloyl group, a benzoyl group,a toluoyl group, a benzyl group, a tetrahydropyranyl group, and amethoxymethyl group are suitable.

In the formula (2), A is an alkylene group having 1 to 4 carbon atoms,preferably an ethylene group or a butylene group, and more preferably anethylene group.

In the formula (2), B is an alkylene group having 1 to 12 carbon atoms,preferably an alkylene group having 1 to 9 carbon atoms, and morepreferably an alkylene group having 2 to 6 carbon atoms.

In the formula (2), R⁷ is —COOR⁸ (wherein R⁸ is a protective group of acarboxyl group), a carboxyl group, or —CH₂OH. As the protective group ofa carboxyl group, a methyl group, an ethyl group, a propyl group, abutyl group, and a benzyl group are suitable. More preferable is amethyl group or an ethyl group.

In the formula (2), Z is —CO—CH═CH—, —CHOH—CH═CH—, —CHOH-1,2-epoxy-,—CO—CH₂CH₂—, —CHOH—CH₂CH₂—, —CO—CH₂CHOH—, —CHOH—CH₂CHOH—, —CO—CH₂CHOR⁹—,—CHOH—CH₂CHOR⁹—, a ketal derivative of —CO—CH═CH—, or a ketal derivativeof —CO—CH₂CH₂— and R⁹ is a lower alkyl group.

Of the compounds represented by the general formula (1), a compoundwherein R³ is —COOR⁴ and Z is —CO—CH═CH— (hereinafter referred to as acompound of the formula (4)) is an intermediate for synthesizing theother compounds represented by the formula (1).

with Regard to Synthetic Methods of the Compound of the formula (4)

The compound of the formula (4) can be synthesized from a compoundrepresented by the formula (7) (hereinafter referred to as a compound ofthe formula (7); the following compounds represented by the otherformulae are also abbreviated in a similar manner). The compound of theformula (7) is obtained by a reaction of a compound of the formula (5)with a compound of the formula (6) to be mentioned below. Moreover, thecompound of the formula (5) can be synthesized from a compound of theformula (10). The compound of the formula (10) is obtained by a reactionof a compound of the formula (8) with a compound of the formula (9) tobe mentioned below.

The compound of the formula (4) can be produced by preparing thefollowing compound of the formula (7) starting from the followingcompound of the formula (5) and the following compound of the formula(6) and further eliminating HX from the following compound of theformula (7).X—CH₂—CH═CH—B—COOR⁴  (5)

In the formula (5), R⁴ represents a protective group of a carboxylgroup, B represents an alkylene group having 1 to 12 carbon atoms, and Xrepresents a benzenesulfonyl group or a toluenesulfonyl group.

In the formula (6), R¹ is a hydrogen atom, a lower alkyl group, or aprotective group of a phenolic hydroxyl group, R² is a hydrogen atom ora protective group of a phenolic hydroxyl group, and A represents analkylene group having 1 to 4 carbon atoms.

In the formula (7), R¹, R², R⁴, A, and B are as defined in the formula(1) and X is as defined in the formula (5).

The compound of the formula (5) can be produced by carrying out arearrangement reaction of the X group of the compound of the formula(10). The compound of the formula (10) can be produced by reacting thefollowing compound of the formula (8) with an alkylmetal compound,followed by reaction with the following compound of the formula (9).CH₂═CH—CH₂—X  (8)

In the formula (8), X is as defined in the formula (5).I—B—COOR⁴  (9)

In the formula (9), R⁴ and B are as defined in the formula (1) and I isan iodine atom.

In the formula (10), R⁴ and B are as defined in the formula (1) and X isas defined in the formula (5).

In the reaction of the compound of the formula (8) with an alkylmetalcompound, the ratio of the alkylmetal compound to the compound of theformula (8) is preferably from 0.7 to 1.3 chemical equivalents, morepreferably from 0.9 to 1.1 chemical equivalents.

The temperature of the above reaction is preferably from −100° C. to 0°C., more preferably from −80° C. to −20° C. When the reactiontemperature is too low, it takes costs to maintain the temperature andwhen the reaction temperature is too high, side reactions may proceed insome cases.

The reaction of the compound of the formula (8) with an alkylmetalcompound is preferably carried out in an aprotic solvent and there canbe suitably used tetrahydrofuran, 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, hexamethylphosphoric triamide,N,N-dimethylpropyleneurea, and mixed solvents thereof.

The reaction time varies depending on conditions but is usually fromseveral minutes to several tens minutes.

As the alkylmetal compound, there may be exemplifed alkyllithiumcompounds such as n-butyllithium, s-butyllithium, t-butyllithium, andphenyllithium; and Grignard compounds such as n-butylmagnesium chloride,s-butylmagnesium chloride, t-butylmagnesium chloride, n-butylmagnesiumbromide, s-butylmagnesium bromide, and t-butylmagnesium bromide, andn-butyllithium, n-butylmagnesium chloride, and n-butylmagnesium bromidecan be suitably used. Moreover, alkali metals such as metal lithium andmetal sodium may be used instead of the alkylmetal compounds.

The compound of the formula (10) can be obtained by subsequentlyreacting the reaction product between the compound of the formula (8)and the alkylmetal compound as mentioned above with the above compoundof the formula (9).

The temperature of the reaction system at the time when the compound ofthe formula (9) is added to the above reaction product is preferablyfrom −100° C. to 0° C., more preferably from −80° C. to −20° C. When thereaction temperature is too low, it takes costs to maintain thetemperature and when the reaction temperature is too high, sidereactions may proceed in some cases.

The reaction time varies depending on conditions but is usually fromseveral minutes to several tens minutes.

After completion of the reaction, the compound of the formula (10) canbe isolated and purified by a known purification method such as solventextraction or column chromatography.

The compound of the formula (5) can be obtained by rearranging the Xgroup in the compound of the formula (10).

As a preferred catalyst for the rearrangement reaction of the compoundof the formula (10), a palladium catalyst can be exemplified. As thepalladium catalyst, there may be suitably usedtetrakistriphenylphosphine palladium(0), a tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, a palladium(II)chloride/triphenylphosphine mixture, a palladium(II)acetate/triphenylphosphine mixture, a palladium(II)acetate/tributylphosphine mixture, or the like is suitably used. Theamount of the palladium catalyst to be used is preferably from 0.0001 to1 mol, more preferably from 0.001 to 0.1 mol relative to 1 mol of thecompound of the formula (10). When the amount of the catalyst is toosmall, the progress of the reaction may be sometimes retarded and whenit is too large, it takes labor to remove the catalyst in some cases.

The rearrangement reaction is preferably carried out in the presence ofa solvent and there can be used tetrahydrofuran, 1,4-dioxane, diethylether, 1,2-dimethoxyethane, toluene, acetonitrile, chloroform,dichloromethane, 1,2-dichloroethane, hexamethylphosphoric triamide,N,N-dimethylpropyleneurea, methanol, ethanol, isopropyl alcohol,ethylene glycol, glycerin, and mixed solvents thereof. Of these, a mixedsolvent of tetrahydrofuran and methanol is suitable.

Suitably, the reaction temperature of the rearrangement reaction ispreferably in the range of 0° C. to 120° C., more preferably 20° C. to100° C. The reaction time varies depending on conditions but is usuallyfrom several hours to several tens hours.

After completion of the reaction, the compound of the formula (5) can beobtained by a known purification method such as solvent extraction orcolumn chromatography.

The compound of the formula (6) can be synthesized according to themethod described in literatures such as G. Solladie, et al., J. Org.Chem., 58, 2181 (1993).

In the compound of the formula (6), R¹ represents a hydrogen atom, alower alkyl group, or a protective group of a phenolic hydroxyl groupand R² represents a hydrogen atom or a protective group of a phenolichydroxyl group. As the lower alkyl group of R¹ in the formula (6)preferably has 1 to 3 carbon atoms and is more preferably a methylgroup.

As the protective group of a phenolic hydroxyl group for R¹ and R² inthe formula (6), easy introduction and removal of the protective groupis preferable and there may be exemplified silyl-type protective groups,acyl-type protective groups, benzyl-type protective groups, ether-typeprotective groups, and the like. Specifically, a t-butyldimethylsilylgroup, a propionyl group, a butyroyl group, an isobutyroyl group, apivaloyl group, a benzoyl group, a toluoyl group, a benzyl group, atetrahydropyranyl group, and a methoxymethyl group are suitable.

In the formula (6), A is an alkylene group having 1 to 4 carbon atoms,preferably an ethylene group or a butylene group, and more preferably anethylene group.

The compound of the formula (7) which is a compound for obtaining thecompound of the formula (4) can be produced by reacting the compound ofthe formula (5) producible by the above method or the like with analkylmetal compound, followed by reaction with the compound of theformula (6).

As the alkylmetal compound, a compound which exerts no adverse effectson the protective group of the carboxyl group in the compound of theformula (5) is preferable and, for example, there can be preferably usedt-butyllithium, lithium diisopropylamide, or lithiumbis(trimethylsilyl)amide.

Basically, the amount of the alkylmetal compound to be used ispreferably from 0.7 to 1.3 chemical equivalents, more preferably from0.9 to 1.1 chemical equivalents relative to the compound of the formula(5).

The above reaction is preferably carried out in an aprotic solvent andthere may be suitably used tetrahydrofuran, 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, hexamethylphosphoric triamide,N,N-dimethylpropyleneurea, and mixed solvents thereof.

The temperature of the reaction of the compound of the formula (5) withthe alkylmetal compound is preferably from −80° C. to 25° C., morepreferably −50° C. to 0° C. The reaction time is usually from severalminutes to several hours.

The compound of the formula (7) can be produced by subsequently reactingthe reaction product between the compound of the formula (5) and thealkylmetal compound as mentioned above with the compound of the formula(6).

The temperature of the reaction system at the time when the compound ofthe formula (6) is added to the reaction product is preferably from−100° C. to 25° C., suitably from −80° C. to 0° C. The reaction time issuitably from several minutes to several hours.

After completion of the reaction, the compound of the formula (7) can beisolated and purified by a known purification method such as solventextraction or column chromatography.

The compound of the formula (4) in the invention can be synthesized bytreating the compound of the formula (7) produced by the above method orthe like with a basic compound in the presence of a metal catalyst whichforms a π-allyl complex.

As the metal catalyst which forms a π-allyl complex, a palladiumcatalyst can be suitably used. Specifically, there may be exemplifiedtetrakistriphenylphosphine palladium(0), a tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, a palladium(II)chloride/triphenylphosphine mixture, a palladium(II)acetate/triphenylphosphine mixture, a palladium(II)acetate/tributylphosphine mixture, and the like. The amount of thepalladium catalyst to be used is preferably from 0.0001 to 1 mol, morepreferably from 0.001 to 0.1 mol relative to 1 mol of the compound ofthe formula (7).

As the above basic compound, tertiary amines such as triethylamine,diisopropylethylamine, N-methylimidazole, and pyridine are suitable. Theamount of the basic compound to be used is 0.9 mol or more, suitablyfrom 1.0 mol to 10 mol relative to 1 mol of the compound of the formula(7).

The above reaction is preferably carried out in the presence of asolvent and there may be used tetrahydrofuran, 1,4-dioxane, diethylether, 1,2-dimethoxyethane, acetonitrile, chloroform, dichloromethane,1,2-dichloroethane, hexamethylphosphoric triamide,N,N-dimethylpropyleneurea, methanol, ethanol, isopropyl alcohol,ethylene glycol, glycerin, and mixed solvents thereof. Of these, a mixedsolvent of 1,2-dichloroethane and an alcohol is suitable.

Suitably, the reaction temperature is preferably from room temperatureto 150° C., more preferably from 50° C. to 120° C.

The reaction time is suitably from several hours to several tens hours.

After completion of the reaction, the compound of the formula (4) can beobtained by a known purification method such as solvent extraction orcolumn chromatography.

Of the compounds of the formula (4), a compound wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is —COOR⁸ and Z is—CO—CH═CH—. When R² in the compound of the formula (4) is a protectivegroup of a phenolic hydroxyl group, the compound wherein R² is ahydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

The method for removing the protective group of a phenolic hydroxylgroup can be performed in accordance with methods well known in thefield of organic synthetic chemistry, e.g., methods described in T. W.Greene., “Protective Groups in Organic Synthesis”, John Wiley & Sons.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —COOR⁴ and Z is —CHOH—CH═CH—(hereinafter referred to as a compound of the formula (11)) can beproduced by reducing the compound of the formula (4) mentioned abovewith a metal-hydrogen complex compound or the like into a hydroxylgroup.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —COOR⁴ and Z is —CHOH-1,2-epoxy-(hereinafter referred to as a compound of the formula (12)) can beproduced by epoxidizing the compound of the formula (11).

The following shows the conversion of the formula (4) into the formula(ii) and the formula (12).

R¹, R², R⁴, A, and B in the formula (11) and the formula (12) are asdefined in the formula (1).

As the metal-hydrogen complex compound at the time when the ketone inthe compound of the formula (4) is reduced into a hydroxyl group,lithium borohydride, sodium borohydride, or the like can be preferablyused. Moreover, the reaction can be also carried out under theconditions of using sodium borohydride and cerium(III) chloride incombination. In the reaction, preferable is the conditions of usingsodium borohydride and cerium(III) chloride in combination. In thereaction, the ratio of the metal-hydrogen complex compound to thecompound of the formula (4) is preferably from 0.5 to 10 chemicalequivalents, more preferably from 1 to 2 chemical equivalents. In thecase that the reduction reaction is carried out under the conditions ofusing sodium borohydride and cerium(III) chloride in combination, theamount of cerium(III) chloride to be used is preferably from 0.01 to 5chemical equivalents, more preferably from 0.1 to 3 chemical equivalentsrelative to the compound of the formula (4).

The above reaction is preferably carried out in the presence of asolvent and there may be used tetrahydrofuran, 1,4-dioxane, diethylether, 1,2-dimethoxyethane, acetonitrile, methanol, ethanol, isopropylalcohol, and mixed solvents thereof.

Suitably, the reaction temperature at the time when the compound of theformula (11) is produced is preferably from −100° C. to 100° C., morepreferably −78° C. to room temperature. The reaction time is suitablyfrom several minutes to several hours. After completion of the reaction,the compound of the formula (11) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (11), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CHOH—CH═CH—. When R² in the compound of the formula (11) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

As the epoxidizing agent at the time when the compound of the formula(12) is produced from the compound of the formula (11), there can besuitably used peracids such as peracetic acid, trifluoroperacetic acid,perbenzoic acid, and m-chloroperbenzoic acid and peroxides such ashydrogen peroxide and t-butyl hydroperoxide. The amount of the peracidsand peroxides to be used is preferably from 1 to 10 chemicalequivalents, more preferably from 1.1 to 2 chemical equivalents.

The above reaction is preferably carried out in the presence of asolvent and there may be used dichloromethane, chloroform,1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, acetonitrile, toluene, water, and mixed solventsthereof.

Suitably, the reaction temperature at the time when the compound of theformula (12) is produced is preferably from −100° C. to 100° C., morepreferably −78° C. to 50° C. The reaction time is suitably from severaltens minutes to several hours. After completion of the reaction, thecompound of the formula (12) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (12), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CHOH-1,2-epoxy-. When R² in the compound of the formula (12) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —COOR⁴ and Z is —CO—CH₂CH₂—(hereinafter referred to as a compound of the formula (13)) can beproduced by catalytically hydrogenating the compound of the formula (4).

Of the compounds represented by the general formula (1), a compoundwherein R³ is —COOR⁴ and Z is —CHOH—CH₂CH₂— (hereinafter referred to asa compound of the formula (14)) can be produced by reducing the compoundof the formula (13) with a metal-hydrogen complex compound.

The following shows the conversion of the formula (4) into the formula(13) and the formula (14).

R¹, R², R⁴, A, and B in the formula (13) and the formula (14) are asdefined in the formula (1).

At the time when the compound of the formula (13) is produced, it ispreferable to use a metal catalyst such as palladium-carbon, platinumoxide (IV), Raney-nickel, platinum black, rhodium-aluminum oxide,triphenylphosphin-rhodium chloride, palladium-barium sulfate, or thelike and render the inside of the reaction vessel under a hydrogenatmosphere. In the reaction, the ratio of the metal catalyst to thecompound of the formula (4) is preferably from 0.01 to 100% by weight,more preferably from 0.1 to 10% by weight.

The production of the compound of the formula (13) is preferably carriedout in the presence of a solvent and there can be used methanol,ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butylalcohol, n-pentane, n-hexane, toluene, ethyl acetate, acetic acid,tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,acetonitrile, N,N-dimethylformamide, N,N-dimethylpropyleneurea, dimethylsulfoxide, water, and mixed solvents thereof.

Suitably, the reaction temperature at the time when the compound of theformula (13) is produced is preferably from 0° C. to 100° C., morepreferably room temperature to 50° C. The reaction time is suitably fromseveral tens minutes to several tens hours. After completion of thereaction, the compound of the formula (13) can be obtained by a knownpurification method such as solvent extraction or column chromatography.

Of the compounds of the formula (13), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CO—CH₂CH₂—. When R² in the compound of the formula (13) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

As the metal-hydrogen complex compound at the time when the compound ofthe formula (14) is produced, preferable is one which does not exert anadverse effect on the protective group of a carboxyl group and lithiumborohydride, sodium borohydride, or the like can be preferably used.More preferable is sodium borohydride. In the reaction, the ratio of themetal-hydrogen complex compound to the compound of the formula (13) ispreferably from 0.5 to 10 chemical equivalents, more preferably from 1to 2 chemical equivalents.

The production of the compound of the formula (14) is preferably carriedout in the presence of a solvent and there may be used tetrahydrofuran,1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, methanol,ethanol, isopropyl alcohol, and mixed solvents thereof.

Suitably, the reaction temperature at the time when the compound of theformula (14) is produced is preferably from −20° C. to 100° C., morepreferably 0° C. to room temperature. The reaction time is suitably fromseveral minutes to several hours. After completion of the reaction, thecompound of the formula (14) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (14), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CHOH—CH₂CH₂—. When R² in the compound of the formula (14) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —COOR⁴ and Z is —CO—CH₂CHOH—(hereinafter referred to as a compound of the formula (15)) can beproduced by adding water molecule to the compound of the formula (4).

Moreover, of the compounds represented by the general formula (1), acompound wherein R³ is —COOR⁴ and Z is —CHOH—CH₂CHOH— (hereinafterreferred to as a compound of the formula (16)) can be produced byreducing the compound of the formula (15) with a metal-hydrogen complexcompound.

The following shows the conversion of the formula (4) into the formula(15) and the formula (16).

R¹, R², R⁴, A, and B in the formula (15) and the formula (16) are asdefined in the formula (1).

At the time when water molecule is added to the compound of the formula(4) for obtaining the formula (15), it is preferable to use a metalhydroxide such as sodium hydroxide or potassium hydroxide as an aqueoussolution. The amount of the metal hydroxide to be used is preferablyfrom 1 to 10 chemical equivalents, more preferably from 2 to 5 chemicalequivalents relative to the compound of the formula (4) Moreover, aphase-transfer catalyst may be also used in combination at that time. Asthe phase-transfer catalyst, there may be preferably used quaternaryammonium salts such as tetrabutylammonium bromide,benzyltributylammonium bromide, and trioctylmethylammonium bromide. Theamount of the phase-transfer catalyst to be used is preferably from0.001 to 1 chemical equivalents, more preferably from 0.01 to 0.2chemical equivalents relative to the compound of the formula (4).

The above reaction is preferably carried out in the presence of asolvent and there may be used tetrahydrofuran, 1,4-dioxane, diethylether, 1,2-dimethoxyethane, acetonitrile, toluene, chloroform,dichloromethane, 1,2-dichloroethane, t-butyl alcohol,N,N-dimethylformamide, N,N-dimethylpropyleneurea, dimethyl sulfoxide,and mixed solvents thereof.

Suitably, the reaction temperature at the time when the compound of theformula (15) is produced is preferably from 0° C. to 150° C., morepreferably room temperature to 100° C. The reaction time is suitablyfrom several hours to several tens hours. After completion of thereaction, the compound of the formula (15) can be obtained by a knownpurification method such as solvent extraction or column chromatography.

In this connection, at the time of the above addition reaction of watermolecule, in the case that R⁴ is an alkyl group such as a methyl groupor an ethyl group, hydrolysis occurs and there is a possibility that R⁴is removed. In such a case, esterification may be carried out afterisolation and purification to synthesize the compound of the formula(15). As the conditions for esterification, the reaction can be carriedout in accordance with methods well known in the field of organicsynthetic chemistry, e.g., methods described in T. W. Greene.,“Protective Groups in Organic Synthesis”, John Wiley & Sons.

Of the compounds of the formula (15), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CO—CH₂CHOH—. When R² in the compound of the formula (15) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

The reducing agent to be used at the time when the compound of theformula (16) is produced is the same as the reducing agent used at thetime when the compound of the formula (14) is produced from the compoundof the formula (13) and is preferably sodium borohydride.

The solvent to be used at the time when the compound of the formula (16)is produced is the same as the solvent used at the time when thecompound of the formula (14) is produced from the compound of theformula (13).

Suitably, the reaction temperature at the time when the compound of theformula (16) is produced is preferably from −20° C. to 100° C., morepreferably 0° C. to room temperature. The reaction time is suitably fromseveral minutes to several hours. After completion of the reaction, thecompound of the formula (16) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (16), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CHOH—CH₂CHOH—. When R² in the compound of the formula (16) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —COOR⁴ and Z is —CO—CH₂CHOR⁵—(hereinafter referred to as a compound of the formula (17)) can beproduced by adding a lower alcohol in the presence of a basic compoundto the compound of the formula (4).

Moreover, of the compounds represented by the general formula (1), acompound wherein R³ is —COOR⁴ and Z is —CHOH—CH₂CHOR⁵— (hereinafterreferred to as a compound of the formula (18)) can be produced byreducing the compound of the formula (17) with a metal-hydrogen complexcompound.

The following shows the conversion of the formula (4) into the formula(17) and the formula (18).

R¹, R², R⁴, A, and B in the formula (17) and the formula (18) are asdefined in the formula (1).

As the basic substance to be used at the time when the compound of theformula (17) is produced from the compound of the formula (4), it ispreferable to use alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide. The amount of the alkali metal hydroxide to be usedis preferably from 1 to 10 chemical equivalents, more preferably from 2to 5 chemical equivalents relative to the compound of the formula (4).The lower alcohol to be used at the time when the compound of theformula (17) is produced from the compound of the formula (4), there maybe mentioned methanol, ethanol, n-propyl alcohol, isopropyl alcohol,n-butyl alcohol, and the like. Moreover, a lower alcohol may be used asa solvent.

Suitably, the reaction temperature at the time when the compound of theformula (17) is produced from the compound of the formula (4) ispreferably from 0° C. to 150° C., more preferably room temperature to100° C. The reaction time is suitably from several hours to several tenshours. After completion of the reaction, the compound of the formula(17) can be obtained by a known purification method such as solventextraction or column chromatography.

In this connection, at the time of the above addition reaction of thelower alcohol, in the case that R⁴ is an alkyl group such as a methylgroup or an ethyl group, hydrolysis occurs and there is a possibilitythat R⁴ is removed. In such a case, esterification may be carried outafter isolation and purification to synthesize the compound of theformula (17). As the conditions for esterification, the reaction can becarried out in accordance with methods well known in the field oforganic synthetic chemistry, e.g., methods described in T. W. Greene.,“Protective Groups in Organic Synthesis”, John Wiley & Sons.

Of the compounds of the formula (17), a compound wherein R is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is —COOR⁸ and Z is—CO—CH₂CHOR⁵—. When R² in the compound of the formula (17) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

The reducing agent to be used at the time when the compound of theformula (18) is produced from the compound of the formula (17) is thesame as the reducing agent used at the time when the compound of theformula (14) is produced from the compound of the formula (13) and ispreferably sodium borohydride.

The solvent to be used at the time when the compound of the formula (18)is produced from the compound of the formula (17) is produced is thesame as the solvent used at the time when the compound of the formula(14) is produced from the compound of the formula (13).

Suitably, the reaction temperature at the time when the compound of theformula (18) is produced from the compound of the formula (17) ispreferably from −20° C. to 100° C., more preferably 0° C. to roomtemperature. The reaction time is suitably from several minutes toseveral hours. After completion of the reaction, the compound of theformula (18) can be obtained by a known purification method such assolvent extraction or column chromatography.

Of the compounds of the formula (18), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis —CHOH—CH₂CHOR⁵—. When R² in the compound of the formula (18) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —COOR⁴ and Z is a ketal derivativeof —CO—CH═CH— (hereinafter referred to as a compound of the formula(19)) can be produced by converting the compound of the formula (4) intoa non-cyclic ketal or cyclic ketal thereof.

In a similar manner, of the compounds represented by the general formula(1), a compound wherein R³ is —COOR⁴ and Z is a ketal derivative of—CO—CH₂CH₂— (hereinafter referred to as a compound of the formula (20))can be produced from the compound of the formula (13).

The following shows the conversion of the formula (4) into the formula(19) and the formula (20).

R¹, R², R⁴, A, and B in the formula (19) and the formula (20) are asdefined in the formula (1), and Y represents a non-cyclic ketal or acyclic ketal.

As the non-cyclic ketal of the formula (19) and the formula (20), theremay be mentioned dimethyl ketals, diacetyl ketals, or the like. As thecyclic ketal of the formula (19) and the formula (20), there may bementioned those obtained from ethylene glycol, 1,3-propanediol, or2,2-dimethyl-1,3-propanediol with a carbonyl group.

The ketalization of the formula (4) can be carried out in accordancewith known methods well known in the field of organic syntheticchemistry, e.g., methods described in T. W. Greene., “Protective Groupsin Organic Synthesis”, John Wiley & Sons.

Of the compounds of the formula (19), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —COOR⁸ and Zis a ketal derivative of —CO—CH═CH—. Moreover, of the compounds of theformula (20), a compound wherein R² is a hydrogen atom represents thesame compound as the compound represented by the general formula (2) ofthe invention wherein R⁷ is —COOR⁸ and Z is a ketal derivative of—CO—CH—CH—.

When R² in the compound of the formula (19) or the compound of theformula (20) is a protective group of a phenolic hydroxyl group, thecompound wherein R² is a hydrogen atom can be obtained by removing theprotective group of a phenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is a carboxyl group and Z is —CO—CH═CH—(hereinafter referred to as a compound of the formula (21)) can beproduced by removing the protective group of the carboxyl group in theabove compound of the formula (4). See, the following scheme.

R¹, R², R⁴, A, and B in the formula (21) are as defined in the formula(1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is—CHOH—CH═CH— (hereinafter referred to as a compound of the formula (22))can be synthesized from the compound of the formula (11) mentionedabove. See, the following scheme.

R¹, R², R⁴, A, and B in the formula (22) are as defined in the formula(1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is—CHOH-1,2-epoxy- (hereinafter referred to as a compound of the formula(23)) can be synthesized from the compound of the formula (12) mentionedabove. See, the following scheme.

R¹, R², R⁴, A, and B in the formula (23) are as defined in the formula(1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is—CHOH—CH₂—CH₂— (hereinafter referred to as a compound of the formula(24)) can be synthesized from the compound of the formula (14) mentionedabove. See, the following scheme.

R¹, R², R⁴, A, and B in the formula (24) are as defined in the formula(1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is—CHOH—CH₂CHOH— (hereinafter referred to as a compound of the formula(25)) can be synthesized from the compound of the formula (16) mentionedabove. See, the following scheme.

R¹, R², R⁴, A, and B in the formula (25) are as defined in the formula(1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is—CO—CH₂CHOR⁵— (hereinafter referred to as a compound of the formula(26)) can be synthesized from the compound of the formula (17) mentionedabove. See, the following scheme.

R¹, R², R⁴, R⁵, A, and B in the formula (26) are as defined in theformula (1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is—CHOH—CH₂CHOR⁵— (hereinafter referred to as a compound of the formula(27)) can be synthesized from the compound of the formula (18) mentionedabove. See, the following scheme.

R¹, R², R⁴, R⁵, A, and B in the formula (27) are as defined in theformula (1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is aketal derivative of —CO—CH═CH— (hereinafter referred to as a compound ofthe formula (28)) can be synthesized from the compound of the formula(19) mentioned above. See, the following scheme.

R¹, R², R⁴, A, B, and Y in the formula (28) are as defined in theformula (1).

Similarly, of the compounds represented by the general formula (1) ofthe invention, a compound wherein R³ is a carboxyl group and Z is aketal derivative of —CO—CH₂CH₂— (hereinafter referred to as a compoundof the formula (29)) can be synthesized from the compound of the formula(20) mentioned above. See, the following scheme.

R¹, R², R⁴, A, B, and Y in the formula (29) are as defined in theformula (1).

The reaction conditions for removing the protective groups from thesecompounds wherein the carboxyl group is protected (protected compounds)vary depending on the kind of the protective groups used. For example,the protective group of the carboxyl group is an ethyl group, it can beremoved in the presence of an alkali catalyst such as sodium hydroxideor potassium hydroxide.

The amount of the above alkali catalyst to be used varies depending onthe structures of R¹, R², and R⁴ of the protected compounds and the kindof the alkali catalysts but is preferably from 1 to 10 chemicalequivalents, more preferably from 2 to 5 chemical equivalents relativeto the protected compound. When the amount of the above alkali catalystto be used is too small, the progress of the reaction is slow in somecases and, when the amount is too large, a large amount of aneutralizing agent is necessary for treatment after the reaction.

In the above reaction, a solvent may be used and there may be suitablyused tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylpropyleneurea, water, methanol,ethanol, isopropyl alcohol, t-butyl alcohol, and mixed solvents thereof.

The reaction temperature of the above reaction is preferably from −20°C. to 80° C., more preferably from 0° C. to 50° C. When the reactiontemperature is too low, the progress of the reaction is low in somecases and when the reaction temperature is too high, side reactions mayproceed in some cases. The reaction time varies depending on conditionsbut is usually from several tens minutes to several hours. Aftercompletion of the reaction, the individual aimed compounds can beobtained by a known purification method such as solvent extraction orcolumn chromatography.

A compound of the compounds of the formula (21) wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CO—CH═CH—. When R² in the compound of the formula (21) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (22) wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CHOH—CH═CH—. When R² in the compound of the formula (22) is aprotective group of a phenolic hydroxyl group, the compound wherein R isa hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (23) wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CHOH-1,2-epoxy-. When R² in the compound of the formula (23) is aprotective group of a phenolic hydroxyl group, the compound wherein R isa hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (24) wherein R is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CHOH—CH—CH—. When R² in the compound of the formula (24) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (25) wherein R is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CHOH—CH₂CHOH—. When R² in the compound of the formula (25) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (26) wherein R is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CO—CH₂CHOR⁵—. When R² in the compound of the formula (26) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (27) wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is —CHOH—CH₂CHOR⁵—. When R² in the compound of the formula (27) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound of the compounds of the formula (28) wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is a ketal derivative of —CO—CH═CH—. When R² in the compound of theformula (28) is a protective group of a phenolic hydroxyl group, thecompound wherein R² is a hydrogen atom can be obtained by removing theprotective group of a phenolic hydroxyl group.

A compound of the compounds of the formula (29) wherein R² is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is a carboxyl group andZ is a ketal derivative of —CO—CH₂CH₂—. When R² in the compound of theformula (29) is a protective group of a phenolic hydroxyl group, thecompound wherein R² is a hydrogen atom can be obtained by removing theprotective group of a phenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is —CHOH—CH═CH—(hereinafter referred to as a compound of the formula (30)) can besynthesized by reducing the ester and ketone of the compound of theformula (4) mentioned above into an alcohol.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is —CHOH-1,2-epoxy-(hereinafter referred to as a compound of the formula (31)) can besynthesized by epoxidizing the compound of the formula (30).

The following shows the conversion of the formula (4) into the formula(30) and the formula (31).

R¹, R², R⁴, A, and B in the formula (30) and the formula (31) are asdefined in the formula (1).

The reaction conditions at the reduction reaction for the production ofthe compound of the formula (30) from the formula (4) vary depending onthe kind of the structures of R¹, R², and R⁴ in the formula (4). Forexample, when the protective group of the carboxylic acid is an ethylgroup, the compound of the formula (30) is obtained by using ametal-hydrogen complex compound or a metal hydride. As themetal-hydrogen complex compound, there may be mentioned lithium aluminumhydride, lithium tributoxyaluminum hydride, sodiumbis(2-methoxyethoxy)aluminum hydride, and the like. Additionally, as themetal hydride, there may be diisobutylaluminum hydride and the like. Inparticular, the reducing agents preferably usable are lithium aluminumhydride and diisobutylaluminum hydride.

The amount of the above reducing agent to be used varies depending onthe structures of R¹, R², and R⁴ in the formula (4) and the kind of thereducing agents but is preferably from 1 to 10 chemical equivalents,more preferably from 2 to 5 chemical equivalents relative to thecompound of the formula (4).

The above reduction reaction is preferably carried out in the presenceof a solvent and there may be used tetrahydrofuran, 1,4-dioxane, diethylether, 1,2-dimethoxyethane, diglyme, toluene, dichloromethane, and mixedsolvents thereof.

Suitably, the reaction temperature at the above reduction reaction ispreferably from −100° C. to 80° C., more preferably −78° C. to roomtemperature. The reaction time is suitably from several minutes toseveral hours. After completion of the reaction, the compound of theformula (30) can be obtained by a known purification method such assolvent extraction or column chromatography.

Of the compounds of the formula (30), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CHOH—CH═CH—. When R² in the compound of the formula (30) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

The epoxidizing agents to be used at the time when the compound of theformula (31) is produced are the same as the epoxidizing agents to beused at the time when the compound of the formula (12) is produced fromthe compound of the formula (11).

The solvents to be used at the time when the compound of the formula(31) is produced are the same as the solvents used at the time when thecompound of the formula (12) is produced from the compound of theformula (11).

Suitably, the reaction temperature at the time when the compound of theformula (31) is produced is preferably from −100° C. to 80° C., morepreferably −78° C. to room temperature. The reaction time is suitablyfrom several tens minutes to several hours. After completion of thereaction, the compound of the formula (31) can be obtained by a knownpurification method such as solvent extraction or column chromatography.

Of the compounds of the formula (31), a compound wherein R is a hydrogenatom represents the same compound as the compound represented by thegeneral formula (2) of the invention wherein R⁷ is —CH₂OH and Z is—CHOH-1,2-epoxy-. When R² in the compound of the formula (31) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is —CHOH—CH₂CHOH—(hereinafter referred to as a compound of the formula (32)) can besynthesized by reducing the compound of the formula (12).

The following shows the conversion from the formula (12) into theformula (32).

R¹, R², R⁴, A, and B in the formula (32) are as defined in the formula(1).

The reducing agents to be used at the time when the compound of theformula (32) is produced from the compound of the formula (12) are thesame as the reducing agents used at the time when the compound of theformula (30) is produced from the compound of the formula (4), and arepreferably lithium aluminum hydride and diisobutylaluminum hydride.

The solvents to be used at the time when the compound of the formula(32) is produced are the same as the solvents used at the time when thecompound of the formula (30) is produced from the compound of theformula (4).

Suitably, the reaction temperature at the above reaction is preferablyfrom −100° C. to 80° C., more preferably −78° C. to room temperature.The reaction time is suitably from several minutes to several hours.After completion of the reaction, the compound of the formula (32) canbe obtained by a known purification method such as solvent extraction orcolumn chromatography.

Of the compounds of the formula (32), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CHOH—CH₂CHOH—. When R² in the compound of the formula (32) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is —CO—CH₂CHOR⁵—(hereinafter referred to as a compound of the formula (34)) can besynthesized by adding a lower alcohol to the compound represented by theformula (33) mentioned below (hereinafter referred to as a compound ofthe formula (33)) in the presence of a basic compound.

The following shows the conversion from the formula (33) into theformula (34).

R¹, R², R⁵, A, and B in the formula (34) are as defined in the formula(1).

The basic compounds to be used at the time when the compound of theformula (34) is produced from the compound of the formula (33) are thesame as the basic compounds used at the time when the compound of theformula (17) is produced from the compound of the formula (4). Moreover,the lower alcohols to be used at the time when the compound of theformula (34) is produced are the same as the lower alcohols used at thetime when the compound of the formula (17) is produced from the compoundof the formula (4).

Suitably, the reaction temperature at the time when the compound of theformula (34) is produced is preferably from 0° C. to 150° C., morepreferably room temperature to 100° C. The reaction time is suitablyfrom several hours to several tens hours. After completion of thereaction, the compound of the formula (34) can be obtained by a knownpurification method such as solvent extraction or column chromatography.

Of the compounds of the formula (34), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CO—CH₂CHOR⁵—. When R² in the compound of the formula (34) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is —CHOH—CH₂CHOR⁵—(hereinafter referred to as a compound of the formula (35)) can besynthesized by reducing the ester or ketone of the compound of theformula (17) mentioned above into an alcohol.

The following shows the conversion from the formula (17) into theformula (35).

R¹, R², R⁴, R⁵, A, and B in the formula (35) are as defined in theformula (1).

The reducing agents to be used at the time when the compound of theformula (35) is produced from the compound of the formula (17) are thesame as the reducing agents used at the time when the compound of theformula (30) is produced from the compound of the formula (4), and arepreferably lithium aluminum hydride and diisobutylaluminum hydride.

The solvents to be used at the time when the compound of the formula(35) is produced are the same as the solvents used at the time when thecompound of the formula (30) is produced from the compound of theformula (4).

Suitably, the reaction temperature at the time when the compound of theformula (35) is produced is preferably from −100° C. to 80° C., morepreferably −78° C. to room temperature. The reaction time is suitablyfrom several minutes to several hours. After completion of the reaction,the compound of the formula (35) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (35), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CHOH—CH₂CHOR⁵—. When R² in the compound of the formula (35) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is a ketal derivativeof —CO—CH═CH— (hereinafter referred to as a compound of the formula(36)) can be synthesized by reducing the ester of the compound of theformula (19) into an alcohol.

Furthermore, the compound of the formula (33) mentioned above can besynthesized by removing the ketal of the compound of the formula (36).

The following shows the conversion from the formula (19) into theformula (34) and the formula (33).

R¹, R², A, B and Y in the formula (33) and the formula (36) are asdefined in the formula (1).

The reducing agents to be used at the time when the compound of theformula (36) is produced from the compound of the formula (19) are thesame as the reducing agents used at the time when the compound of theformula (30) is produced from the compound of the formula (4), and arepreferably lithium aluminum hydride and diisobutylaluminum hydride.

The solvents to be used at the time when the compound of the formula(36) is produced are the same as the solvents used at the time when thecompound of the formula (30) is produced from the compound of theformula (4).

Suitably, the reaction temperature at the time when the compound of theformula (36) is produced is preferably from −100° C. to 80° C., morepreferably −78° C. to room temperature. The reaction time is suitablyfrom several minutes to several hours. After completion of the reaction,the compound of the formula (36) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (36), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis a ketal derivative of —CO—CH═CH—. When R² in the compound of theformula (36) is a protective group of a phenolic hydroxyl group, thecompound wherein R² is a hydrogen atom can be obtained by removing theprotective group of a phenolic hydroxyl group.

The reaction for removing the ketal from the compound of the formula(36) can be carried out in accordance with known methods well known inthe field of organic synthetic chemistry, e.g., methods described in T.W. Greene., “Protective Groups in Organic Synthesis”, John Wiley & Sons,whereby the compound of the formula (33) can be obtained.

Of the compounds of the formula (33), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CO—CH═CH—. When R² in the compound of the formula (33) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Of the compounds represented by the general formula (1) of theinvention, a compound wherein R³ is —CH₂OH and Z is a ketal derivativeof —CO—CH₂CH₂— (hereinafter referred to as a compound of the formula(37)) can be synthesized by reducing the ester of the compound of theformula (20) into an alcohol.

Furthermore, a compound represented by the formula (38) (hereinafterreferred to as a compound of the formula (38)) can be synthesized byremoving the ketal of the compound of the formula (37).

The following shows the conversion from the formula (20) into theformula (37) and the formula (38).

R¹, R², A, B, and Y in the formula (37) and the formula (38) are asdefined in the formula (1).

The reducing agents to be used at the time when the compound of theformula (37) is produced from the compound of the formula (20) are thesame as the reducing agents used at the time when the compound of theformula (30) is produced from the compound of the formula (4), and arepreferably lithium aluminum hydride and diisobutylaluminum hydride.

The solvents to be used at the time when the compound of the formula(37) is produced are the same as the solvents used at the time when thecompound of the formula (30) is produced from the compound of theformula (4).

Suitably, the reaction temperature at the time when the compound of theformula (37) is produced is preferably from −100° C. to 80° C., morepreferably −78° C. to room temperature. The reaction time is suitablyfrom several minutes to several hours. After completion of the reaction,the compound of the formula (37) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (37), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis a ketal derivative of —CO—CH—CH—. When R² in the compound of theformula (37) is a protective group of a phenolic hydroxyl group, thecompound wherein R² is a hydrogen atom can be obtained by removing theprotective group of a phenolic hydroxyl group.

The reaction for removing the ketal from the compound of the formula(37) can be carried out in accordance with known methods well known inthe field of organic synthetic chemistry, e.g., methods described in T.W. Greene., “Protective Groups in Organic Synthesis”, John Wiley & Sons,whereby the compound of the formula (38) can be obtained.

Of the compounds of the formula (38), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CO—CH₂CH₂—. When R² in the compound of the formula (38) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

A compound represented by the general formula (38) (hereinafter referredto as a compound of the formula (39)) can be synthesized by removing theprotective group of the carboxyl group from the compound of the formula(13) of the invention.

Similarly, a compound represented by the general formula (40)(hereinafter referred to as a compound of the formula (40)) can besynthesized from the compound of the formula (15) of the invention byremoving the protective group of the carboxyl group.

The following shows the conversion from the formula (13) into theformula (39) and the conversion from the formula (15) into the formula(40).

R¹, R², A, and B in the formula (39) and the formula (40) are as definedin the formula (1).

The reaction conditions to be used at the time when the compound of theformula (39) is produced from the compound of the formula (13) and thecompound of the formula (40) is produced from the compound of theformula (15) are the same as the reaction conditions at the time whenthe compound of the formula (21) is produced from the compound of theformula (4).

The solvents to be used at the time when the compound of the formula(39) and the compound of the formula (40) are produced are the same asthe solvents used at the time when the compound of the formula (21) isproduced from the compound of the formula (4).

Suitably, the reaction temperature at the time when the compound of theformula (39) and the compound of the formula (40) are produced ispreferably from −20° C. to 80° C., more preferably 0° C. to 50° C. Whenthe reaction temperature is too low, the progress of the reaction is lowin some cases and when the reaction temperature is too high, sidereactions may proceed in some cases. The reaction time varies dependingon conditions but is usually from several tens minutes to several hours.After completion of the reaction, the respective aimed compounds can beobtained by a known purification method such as solvent extraction orcolumn chromatography.

Of the compounds of the formula (39), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is a carboxylgroup and Z is —CO—CH₂CH₂—. When R² in the compound of the formula (39)is a protective group of a phenolic hydroxyl group, the compound whereinR² is a hydrogen atom can be obtained by removing the protective groupof a phenolic hydroxyl group.

Of the compounds of the formula (40), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is a carboxylgroup and Z is —CO—CH₂CHOH—. When R² in the compound of the formula (40)is a protective group of a phenolic hydroxyl group, the compound whereinR² is a hydrogen atom can be obtained by removing the protective groupof a phenolic hydroxyl group.

By reducing the compounds of the formula (13) of the invention, acompounds represented by the formula (41) (hereinafter referred to as acompound of the formula (41)) can be synthesized.

The following shows the conversion from the formula (13) into theformula (41).

R¹, R², A, and B in the formula (41) are as defined in the formula (1).

The reducing agents to be used at the time when the compound of theformula (41) is produced from the compound of the formula (13) are thesame as the reducing agents used at the time when the compound of theformula (30) is produced from the compound of the formula (4), and arepreferably lithium aluminum hydride and diisobutylaluminum hydride.

The solvents to be used at the time when the compound of the formula(41) is produced are the same as the solvents used at the time when thecompound of the formula (30) is produced from the compound of theformula (4).

Suitably, the reaction temperature at the time when the compound of theformula (41) is produced is preferably from −100° C. to 80° C., morepreferably −78° C. to room temperature. The reaction time is suitablyfrom several minutes to several hours. After completion of the reaction,the compound of the formula (41) can be obtained by a known purificationmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (41), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CHOH—CH₂CH₂—. When R² in the compound of the formula (41) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

By adding water molecule to the compounds of the formula (33) of theinvention, a compounds represented by the general formula (42)(hereinafter referred to as a compound of the formula (42)) can beobtained.

The following shows the conversion from the formula (33) into theformula (42).

R¹, R², A, and B in the formula (42) are as defined in the formula (1).

The reaction conditions at the time when the compound of the formula(42) is produced from the compound of the formula (33) are the same asthe reaction conditions used at the time when the compound of theformula (15) is produced from the compound of the formula (4).

The solvents to be used at the time when the compound of the formula(42) is produced are the same as the solvents used at the time when thecompound of the formula (15) is produced from the compound of theformula (4).

Suitably, the reaction temperature at the time when the compound of theformula (42) is produced is preferably from 0° C. to 150° C., morepreferably room temperature to 100° C. The reaction time is suitablyfrom several hours to several tens hours. After completion of thereaction, the compound of the formula (42) can be obtained by a knownmethod such as solvent extraction or column chromatography.

Of the compounds of the formula (42), a compound wherein R² is ahydrogen atom represents the same compound as the compound representedby the general formula (2) of the invention wherein R⁷ is —CH₂OH and Zis —CO—CH₂CHOH—. When R² in the compound of the formula (42) is aprotective group of a phenolic hydroxyl group, the compound wherein R²is a hydrogen atom can be obtained by removing the protective group of aphenolic hydroxyl group.

Among the compounds represented by the general formulae (1) and (2) ofthe invention, there are compounds having one or two asymmetric carbons.They are usually obtained as racemic mixtures, but it is possible toseparate and use only one optical isomer by a method of synthesizingonly one optical isomer through asymmetric synthesis or a method of highperformance liquid chromatography using an optically active column, orthe like, if necessary.

The compounds represented by the general formula (1) and the compoundsrepresented by the general formula (2) according to the invention caninhibit activity of tyrosinase which is an oxidase of L-tyrosine.Moreover, the compounds represented by the general formula (1) and thecompounds represented by the general formula (2) are considered to havealso an action of scavenging hydroxy radicals and an activity ofsuppressing formation of lipid peroxide. In this connection, in the casethat R¹ is a lower alkyl group or a protective group of a phenolichydroxyl group and R² is a protective group of a phenolic hydroxyl groupin the compounds represented by the formula (1), these activities do notexhibited sometimes in vitro. For such a compounds, these activities canbe expected in vivo.

From this fact, it is predicted that suppression of the formation ofmelanin pigment and suppression of pigmentation onto skin and the likeare possible. All of these compounds can be used with mixing intoformulations of foods, medicines, quasi-drugs, cosmetics, etc. In thecase that they are used as skin external preparations for the purpose ofpreventing and improving spots and freckles, it is preferable to mixthem into toilet water, liquid cosmetics, milky lotions, creams, packs,and the like.

Moreover, since the compounds represented by the general formula (2)exhibit an effect of inhibiting hyaluronic acid-degrading enzyme andfurther an effect of scavenging free radicals and an effect ofsuppressing formation of lipid peroxide, they can be suitably used withmixing into formulations of foods, medicines, quasi-drugs, cosmetics,etc.

The compounds 6, 12, 17, 22, 26, 27, 28, 29, 30, 31, 32 and/or 33 can beused as tyrosinase activity inhibitors, hyaluronic acid-degrading enzymeinhibitors, antioxidants, hydroxy radical scavengers, and/or lipidperoxide formation suppressors.

The compounds 7, 8, 13, 18, 19, 23, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, and/or 48 can be used as tyrosinase activityinhibitors, hyaluronic acid-degrading enzyme inhibitors, antioxidants,hydroxy radical scavengers, and/or lipid peroxide formation suppressors.

EXAMPLES

The following will describe the invention in detail with reference toExamples but the invention is not limited to these Examples. In thisconnection, Ts represents a p-toluenesulfonyl group.

Synthetic Example 1

As a starting material for synthesizing the compound of the formula (4)of the invention, the compound 5 was prepared via the compound 2 and thecompound 3 using the compound 1 as a starting material.

In this connection, the compound 1 corresponds to the compound of theformula (8), the compound 2 to the compound of the formula (10), thecompound 3 to the compound of the formula (5), the compound 4 to thecompound of the formula (6), and the compound 5 to the compound of theformula (7).

First, conversion of ethyl 6-bromohexanoate into ethyl 6-iodohexanoatewas carried out. Namely, 39.1 g (175 mmol) of ethyl 6-bromohexanoate wasdissolved in 250 ml of acetone, and 29.1 g (175 mmol) of potassiumiodide was added thereto, followed by heating under reflux over a periodof 20 hours. Then, after the reaction solution was allowed to cool toroom temperature, the solvent was removed by distillation and theresidue was extracted with 150 ml of ethyl acetate. The resultingorganic layer was washed with 50 ml of distilled water and then driedover anhydrous magnesium sulfate. After drying, 47.4 g of a crudeproduct was obtained by removing the solvent by distillation and dryingunder reduced pressure. As a result of ¹H-NMR analysis thereof, it wasfound that the crude product contained ethyl 6-iodohexanoate in a molarfraction of about 90%. The crude product was used in the following stepwithout further purification.

Next, 30.5 g (155 mmol) of the compound 1 was dissolved in 450 ml oftetrahydrofuran, and the resulting solution was cooled to −78° C. withdry ice/acetone. To the resulting solution was dropwise added 100 ml(156 mmol) of 1.56 M n-butyllithium/n-hexane solution. After theresulting mixture was stirred at the same temperature for 45 minutes, asolution of the crude product of ethyl 6-iodohexanoate prepared in theabove, which had been dissolved in 50 ml of tetrahydrofuran, wasdropwise added to the mixture. After dropwise addition, the resultingmixture was stirred at the same temperature for 10 minutes and then, thetemperature was gradually elevated. When the temperature of the reactionsolution reached −10° C., 50 ml of 5% citric acid aqueous solution wasadded to terminate the reaction. To the reaction mixture were added 100ml of 10% sodium thiosulfate aqueous solution, 150 ml of saturatedsodium chloride aqueous solution, and 50 ml of ethyl acetate, followedby partitioning. The organic layer was separated and the aqueous layerwas extracted in 50 ml of ethyl acetate. The combined organic layer wasdried over anhydrous magnesium sulfate. After drying, the solvent wasremoved by distillation and purification by silica gel columnchromatography was carried out to obtain 49.5 g (yield 94%) of a paleyellow, liquid compound having a low viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.20-1.70 (9H, m), 2.03-2.15 (2H,m), 2.23-2.35 (2H, m), 2.44 (3H, s), 3.43-3.55 (1H, m), 4.11 (2H, q),5.04 (1H, d), 5.25-5.35 (1H, m), 5.53-5.68 (1H, m), 7.32 (2H, d), 7.70(2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2930, 2860, 1730, 1600, 1300, 1290,1180, 1140, 940, 670.

The results of elemental analysis were as follows: carbon 64.09% andhydrogen 7.87%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 2.

Next, conversion from the compound 2 to the compound 3 was carried out.

Into 360 ml of tetrahydrofuran and 120 ml of methanol was dissolved 49.5g (146 mmol) of the compound 2, and 3.38 g (2.92 mmol) oftetrakistriphenylphosphine palladium was added. The reaction solutionwas heated under reflux over a period of 16 hours. Then, after thereaction solution was allowed to cool to room temperature, the solventwas removed by distillation and purification by silica gelchromatography was carried out to obtain 47.1 g (95%) of a pale brown,liquid compound having a low viscosity. As a result of ¹H-NMR analysis,IR absorption spectrum analysis, and elemental analysis shown below, itwas confirmed that the product contained the compound 3 in a molarfraction of 73% and the remaining 27% was a geometrical isomer whereinthe carbon-carbon double bond in the compound 3 was arranged in acis-form.

The chemical shift values of the compound 3 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.20-1.33 (7H, m),1.50-1.60 (2H, m), 1.99 (2H, t), 2.20-2.30 (2H, m), 2.45 (3H, s), 3.73(2H, d), 4.08-4.15 (2H, q), 5.35-5.55 (2H, m), 7.34 (2H, d), 7.72 (2H,d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2930, 2860, 1730, 1600, 1320, 1150,1090, 1030, 820, 740.

The results of elemental analysis were as follows: carbon 64.03% andhydrogen 7.57%.

Next, conversion from the compound 3 to the compound 5 was carried out.

A solution of 8.75 g (25.8 mmol) of the compound 3 dissolved in 75 ml oftetrahydrofuran was cooled to −78° C. with dry ice/acetone. To thesolution was dropwise added 13.0 ml (26.0 mmol) of 2.0 M lithiumdiisopropylamide/heptane-tetrahydrofuran-ethylbenzene solution. Afterthe resulting mixture was stirred at the same temperature for 60minutes, a solution of 7.34 g (25.8 mmol) of the compound 4 dissolved in30 ml of tetrahydrofuran was dropwise added thereto. After dropwiseaddition, the resulting mixture was stirred at the same temperature for30 minutes and then, the temperature was gradually elevated. When thetemperature of the reaction solution reached −30° C., a solutionobtained by dissolving 3.0 g of citric acid in 10 ml of methanol wasadded to terminate the reaction. To the reaction mixture were added 30ml of distilled water, 50 ml of saturated sodium chloride aqueoussolution, and 50 ml of ethyl acetate, followed by partitioning. Theorganic layer was separated and the aqueous layer was extracted with 50ml of ethyl acetate. The combined organic layer was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation andpurification by silica gel column chromatography was carried out toobtain 6.15 g (yield 38%) of a pale yellow, liquid compound having amedium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.25 (3H, t), 1.44-2.04 (10H, m),2.15-2.29 (2H, m), 2.45 (3H, s), 2.57-3.00 (2H, m), 3.12-4.62 (8H, m),4.95-5.83 (2H, m), 6.71-6.88 (2H, m), 6.97-7.06 (1H, m), 7.34 (2H, d),7.45-7.54 (2H, m), 7.58-7.77 (3H, m), 8.20 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3510, 2940, 2860, 1740, 1600, 1510,1290, 1270, 1200, 1140, 1061, 1030, 710.

The results of elemental analysis were as follows: carbon 67.27% andhydrogen 6.95%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 5.

Example 1

Starting from the compound 5 obtained in the above Synthetic Example 1,the compound 6 of the invention was prepared.

To a solution of 5.00 g (8.03 mmol) of the compound 5 dissolved in 120 gof 1,2-dichloroethane, 40 g of isopropyl alcohol, and 40 g of glycerinwere added 3.40 ml (24.4 mmol) of triethylamine, 105 mg (0.400 mmol) oftriphenylphosphine, and 462 mg (0.400 mmol) oftetrakistriphenylphosphine palladium, followed by stirring at a bathtemperature of 100° C. for 16 hours. After cooling and concentration,100 ml of distilled water, 50 ml of saturated sodium chloride aqueoussolution, and 50 ml of ethyl acetate were added thereto, followed bypartitioning. The organic layer was separated and washed with 30 ml ofsaturated sodium chloride aqueous solution. The combined aqueous layerwas extracted with 30 ml of ethyl acetate. The combined organic layerwas dried over anhydrous magnesium sulfate. The solvent was removed bydistillation and purification by silica gel column chromatography wascarried out to obtain 1.45 g (yield 39%) of a pale yellow, liquidcompound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.25 (3H, t), 1.30-1.53 (6H, m),1.57-1.67 (2H, m), 2.16-2.32 (4H, m), 2.84-3.00 (4H, m), 3.80 (3H, s),4.12 (2H, q), 6.11 (1H, d), 6.77-6.88 (3H, m), 7.05 (1H, d), 7.46-7.53(2H, m), 7.59-7.67 (1H, m), 8.21 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2930, 2860, 1730, 1700, 1670, 1630,1600, 1510, 1270, 1200, 1150, 1060, 1030, 710.

The results of elemental analysis were as follows: carbon 71.81% andhydrogen 7.25%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 6.

Example 2

Starting from the compound 6 obtained in the above Synthetic Example 1,the compound 7 of the invention was prepared.

To a solution of 467 mg (1.00 mmol) of the compound 6 dissolved in 7 mlof 1,4-dioxane was added 3 ml of 1N sodium hydroxide aqueous solution,followed by stirring. After 4 hours of stirring, 3 ml of 1N hydrochloricacid was added to neutralize the mixture. To the reaction solution wasadded 30 ml of saturated sodium chloride aqueous solution and extractionwith 10 ml of chloroform was repeated three times. The combined organiclayer was dried over anhydrous magnesium sulfate and then concentrated.The obtained residue was purified by silica gel column chromatography toobtain 174 mg (52%) of a colorless crystalline compound.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.50 (6H, m), 1.57-1.69 (2H,m), 2.19 (2H, q), 2.34 (2H, t), 2.79-2.90 (4H, m), 3.87 (3H, s), 6.08(1H, d), 6.64-6.85 (4H, m).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3530, 2930, 2850, 1700, 1660, 1640,1520, 1280, 1230, 1030.

The results of elemental analysis were as follows: carbon 68.48% andhydrogen 8.11%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 7.

Example 3

Starting from the compound 6 obtained in Example 1, a mixture of thecompound 7 and the compound 8 of the invention was prepared.

To a solution of 467 mg (1.00 mmol) of the compound 6 dissolved in 7 mlof ethanol was added 3 ml of 1N sodium hydroxide aqueous solution. After3 hours of stirring, 3 ml of 1N hydrochloric acid was added to terminatethe reaction. To the reaction solution was added 30 ml of saturatedsodium chloride aqueous solution and extraction with 10 ml of chloroformwas repeated three times. The combined organic layer was dried overanhydrous magnesium sulfate and then concentrated. The obtained residuewas purified by silica gel column chromatography to obtain 237 mg of apale yellow, liquid compound having a medium viscosity.

As a result of analyzing ¹H-NMR spectrum as measured indeuterochloroform, it was confirmed that the product was a mixture ofthe compound 7 and the compound 8 wherein ethanol used as the solventwas added to the double bond of the compound 7 (existing molar ratio ofthe compound 7 to the compound 8 was 35:65). Incidentally, the chemicalshift value of the ethoxy group in the compound 8 was 1.12 (3H, t) and3.35-3.50 (2H, m) and the chemical shift value of CH to which the ethoxygroup was bonded was 3.68-3.78 (1H, m).

Synthetic Example 2

As a starting material for obtaining the compound of the formula (4),starting from the compound 1 as in Synthetic Example 1, the compound 11was prepared via the compound 9 and the compound 10.

First, conversion of ethyl 4-bromobutyrate into ethyl 4-iodobutyrate wascarried out.

Into 250 ml of acetone was dissolved 34.2 g (175 mmol) of ethyl4-bromobutyrate, and then 29.1 g (175 mmol) of potassium iodide wasadded thereto, followed by heating under reflux over a period of 20hours. Then, after the reaction solution was allowed to cool to roomtemperature, the solvent was removed by distillation and the residue wasextracted with 150 ml of ethyl acetate. The resulting organic layer waswashed with 50 ml of distilled water and then dried over anhydrousmagnesium sulfate. Then, 43.2 g of a crude product was obtained byremoving the solvent by distillation and drying under reduced pressure.As a result of ¹H-NMR analysis, it was found that the crude productcontained ethyl 4-iodobutyrate in a molar fraction of 92%. The crudeproduct was used in the following step as it was.

Next, 30.5 g (155 mmol) of the compound 1 was dissolved in 450 ml oftetrahydrofuran, and the resulting solution was cooled to −78° C. withdry ice/acetone. To the resulting solution was dropwise added 100 ml(156 mmol) of 1.56 M n-butyllithium/n-hexane solution. After theresulting mixture was stirred at the same temperature for 45 minutes, asolution of the crude product of ethyl 4-iodobutyrate, which had beenprepared as above and dissolved in 50 ml of tetrahydrofuran, wasdropwise added to the mixture. After dropwise addition, the resultingmixture was stirred at the same temperature for 10 minutes and then, thetemperature was gradually elevated. When the temperature of the reactionsolution reached −10° C., 50 ml of 5% citric acid aqueous solution wasadded to terminate the reaction. To the reaction mixture were added 100ml of 10% sodium thiosulfate aqueous solution, 150 ml of saturatedsodium chloride aqueous solution, and 50 ml of ethyl acetate, followedby partitioning. The organic layer was separated and the aqueous layerwas extracted in 50 ml of ethyl acetate. The combined organic layer wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation and purification by silica gel column chromatography wascarried out to obtain 46.0 g (yield 96%) of a pale yellow, liquidcompound having a low viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23 (3H, t), 1.52-1.63 (1H, m),1.65-1.80 (2H, m), 2.07-2.15 (1H, m), 2.25-2.37 (2H, m), 2.44 (3H, s),3.45-3.55 (1H, m), 4.10 (2H, q), 5.08 (1H, d), 5.31 (1H, d), 5.57-5.66(1H, m), 7.32 (2H, d), 7.70 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2980, 2930, 1730, 1600, 1300, 1290,1140, 1090, 820, 670.

The results of elemental analysis were as follows: carbon 61.73% andhydrogen 6.92%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 9.

Next, conversion from the compound 9 to the compound 10 was carried out.

Into 360 ml of tetrahydrofuran and 120 ml of methanol was dissolved 46.0g (148 mmol) of the compound 9, and 3.42 g (2.96 mmol) oftetrakistriphenylphosphine palladium was added. The reaction solutionwas heated under reflux over a period of 16 hours. Then, after thereaction solution was allowed to cool to room temperature, the solventwas removed by distillation and purification by silica gelchromatography was carried out to obtain 41.0 g (89%) of a pale brown,liquid compound having a low viscosity. As a result of ¹H-NMR analysis,IR absorption spectrum analysis, and elemental analysis shown below, itwas confirmed that the product contained the compound 10 in a molarfraction of 81% and the remaining 19% was a geometrical isomer whereinthe carbon-carbon double bond in the compound 10 was arranged in acis-form.

The chemical shift values of the compound 10 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.25 (3H, t), 1.57-1.65(2H, m), 2.03-2.10 (2H, m), 2.20 (2H, t), 2.44 (3H, s), 3.73 (2H, d),4.12 (2H, q), 5.37-5.55 (2H, m), 7.33 (2H, d), 7.73 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2980, 2930, 1730, 1600, 1320, 1300,1150, 1090, 820, 740.

The results of elemental analysis were as follows: carbon 61.81% andhydrogen 7.01%.

The compound 11 was prepared from the compound 10.

A solution of 6.63 g (21.4 mmol) of the compound 10 dissolved in 65 mlof tetrahydrofuran was cooled to −78° C. with dry ice/acetone. To thesolution was dropwise added 11.0 ml (22.0 mmol) of 2.0 M lithiumdiisopropylamide/heptane-tetrahydrofuran-ethylbenzene solution. Afterthe resulting mixture was stirred at the same temperature for 60minutes, a solution of 6.09 g (21.4 mmol) of the compound 4 dissolved in25 ml of tetrahydrofuran was dropwise added thereto. After dropwiseaddition, the resulting mixture was stirred at the same temperature for30 minutes and then, the temperature was gradually elevated. When thetemperature of the reaction solution reached −20° C., a solutionobtained by dissolving 3.0 g of citric acid in 10 ml of methanol wasadded to terminate the reaction. To the reaction mixture were added 30ml of distilled water, 50 ml of saturated sodium chloride aqueoussolution, and 50 ml of ethyl acetate, followed by partitioning. Theorganic layer was separated and the aqueous layer was extracted with 50ml of ethyl acetate. The combined organic layer was dried over anhydrousmagnesium sulfate. The solvent was removed by distillation andpurification by silica gel column chromatography was carried out toobtain 4.33 g (yield 34%) of a pale yellow, liquid compound having amedium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.24 (3H, t), 1.38-2.50 (11H, m),2.59-3.00 (2H, m), 3.15-4.58 (8H, m), 5.08-5.86 (2H, m), 6.69-6.91 (2H,m), 7.00-7.12 (1H, m), 7.28-7.38 (2H, m), 7.45-7.55 (2H, m), 7.58-7.79(3H, m), 8.21 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3510, 2940, 1730, 1600, 1510, 1290,1270, 1150, 1060, 710.

The results of elemental analysis were as follows: carbon 66.53% andhydrogen 6.58%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 11.

Example 4

Starting from the compound 11 obtained in the above Synthetic Example 2,the compound 12 of the invention was prepared.

To a solution of 3.57 g (6.00 mmol) of the compound 11 dissolved in 90 gof 1,2-dichloroethane, 30 g of isopropyl alcohol, and 30 g of glycerinwere added 2.50 ml (17.9 mmol) of triethylamine, 78.7 mg (0.300 mmol) oftriphenylphosphine, and 347 mg (0.300 mmol) oftetrakistriphenylphosphine palladium, followed by stirring at a bathtemperature of 100° C. for 16 hours. After cooling and concentration, 80ml of distilled water, 40 ml of saturated sodium chloride aqueoussolution, and 40 ml of ethyl acetate were added thereto, followed bypartitioning. The organic layer was separated and washed with 25 ml ofsaturated sodium chloride aqueous solution. The combined aqueous layerwas extracted with 25 ml of ethyl acetate. The combined organic layerwas dried over anhydrous magnesium sulfate. The solvent was removed bydistillation and purification by silica gel column chromatography wascarried out to obtain 613 mg (yield 23%) of a pale yellow, liquidcompound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.25 (3H, t), 1.46-1.56 (2H, m),1.61-1.72 (2H, m), 2.21-2.35 (4H, m), 2.86-3.00 (4H, m), 3.80 (3H, s),4.13 (2H, q), 6.12 (1H, d), 6.77-6.87 (3H, m), 7.03-7.08 (1H, d),7.47-7.54 (2H, m), 7.59-7.66 (1H, m), 8.21 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2940, 1740, 1670, 1630, 1600, 1510,1270, 1200, 1150, 1060, 710.

The results of elemental analysis were as follows: carbon 70.91% andhydrogen 7.17%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 12.

Example 5

Starting from the compound 12 obtained in the above Example 4, thecompound 13 of the invention was prepared.

To a solution of 439 mg (1.00 mmol) of the compound 12 dissolved in 7 mlof 1,4-dioxane was added 3 ml of 1N sodium hydroxide aqueous solution,followed by stirring. After 4 hours of stirring, 3 ml of 1N hydrochloricacid was added to neutralize the mixture. To the reaction solution wasadded 30 ml of saturated sodium chloride aqueous solution and extractionwith 10 ml of chloroform was repeated three times. The combined organiclayer was dried over anhydrous magnesium sulfate and then concentrated.The obtained residue was purified by silica gel column chromatography toobtain 90.0 mg (29%) of a pale yellow, liquid compound having a mediumviscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.46-1.56 (2H, m), 1.60-1.72 (2H,m), 2.23 (2H, q), 2.38 (2H, t), 2.79-2.91 (4H, m), 3.86 (3H, s), 6.10(1H, d), 6.64-6.85 (4H, m).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3400, 2940, 1710, 1660, 1630, 1520,1270, 1240, 1150, 1030, 820, 720.

The results of elemental analysis were as follows: carbon 66.90% andhydrogen 7.11%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 13.

Synthetic Example 3

As a starting material for obtaining the compound of the formula (4) ofthe invention, starting from the compound 1 as in Synthetic Example 1,the compound 16 was prepared via the compound 14 and the compound 15.

First, conversion from the compound 1 to the compound 14 was carriedout.

A solution of 4.91 g (25.0 mmol) of the compound 1 and 656 mg (2.50mmol) of triphenylphosphine dissolved in 80 ml of toluene was cooled to−78° C. with dry ice/acetone. To the solution was dropwise added 13.0 ml(26.0 mmol) of 2.0 M lithiumdiisopropylamide/heptane-tetrahydrofuran-ethylbenzene solution. Afterthe resulting mixture was stirred at the same temperature for 30minutes, a solution of 3.00 ml (27.7 mmol) of the ethyl acrylatedissolved in 15 ml of toluene was dropwise added thereto. After dropwiseaddition, the resulting mixture was stirred at the same temperature for30 minutes, a solution obtained by dissolving 3.0 g of citric acid in 10ml of methanol was added to terminate the reaction. To the reactionmixture were added 60 ml of saturated sodium chloride aqueous solutionand 50 ml of ethyl acetate, followed by partitioning. The organic layerwas separated and the aqueous layer was extracted with 20 ml of ethylacetate. The combined organic layer was dried over anhydrous magnesiumsulfate. The solvent was removed by distillation and purification bysilica gel column chromatography was carried out to obtain 2.99 g (yield40%) of a pale yellow, liquid compound having a low viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23 (3H, t), 1.80-2.00 (1H, m),2.30-2.49 (6H, m), 3.64 (1H, dt), 4.10 (2H, d), 5.10 (1H, m), 5.33 (1H,d), 5.56-5.68 (1H, m), 7.33 (2H, d), 7.71 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2980, 1730, 1600, 1380, 1290, 1150,1090, 940, 820, 670.

The results of elemental analysis were as follows: carbon 60.97% andhydrogen 6.75%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 14.

Next, conversion from the compound 14 to the compound 15 was carriedout.

Into 36 ml of tetrahydrofuran and 12 ml of methanol was dissolved 4.75 g(16.0 mmol) of the compound 14, and 277 mg (0.240 mmol) oftetrakistriphenylphosphine palladium was added. The reaction solutionwas heated under reflux over a period of 6 hours. Then, after thereaction solution was allowed to cool to room temperature, the solventwas removed by distillation and purification by silica gelchromatography was carried out to obtain 3.64 g (77%) of a pale brown,liquid compound having a low viscosity. As a result of ¹H-NMR analysis,IR absorption spectrum analysis, and elemental analysis shown below, itwas confirmed that the product contained the compound 15 in a molarfraction of 83% and the remaining 17% was a geometrical isomer whereinthe carbon-carbon double bond in the compound 15 was arranged in acis-form.

The chemical shift values of the compound 15 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.25 (3H, t), 2.22-2.38(4H, m), 2.45 (3H, s), 3.73 (2H, d), 4.12 (2H, q), 5.40-5.59 (2H, m),7.34 (2H, d), 7.72 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2980, 2930, 1730, 1600, 1320, 1300,1180, 1150, 1090, 820, 740.

The results of elemental analysis were as follows: carbon 60.54% andhydrogen 7.67%.

Next, conversion from the compound 15 to the compound 16 was carriedout.

Namely, a solution of 3.64 g (12.3 mmol) of the compound 15 dissolved in50 ml of tetrahydrofuran was cooled to −78° C. with dry ice/acetone. Tothe solution was dropwise added 6.80 ml (13.6 mmol) of 2.0 M lithiumdiisopropylamide/heptane-tetrahydrofuran-ethylbenzene solution. Afterthe resulting mixture was stirred at the same temperature for 60minutes, a solution of 3.85 g (13.5 mmol) of the compound 4 dissolved in20 ml of tetrahydrofuran was dropwise added thereto. After dropwiseaddition, the resulting mixture was stirred at the same temperature for30 minutes and then, the temperature was gradually elevated. When thetemperature of the reaction solution reached −15° C., a solutionobtained by dissolving 1.0 g of citric acid in 5 ml of methanol wasadded to terminate the reaction. To the reaction mixture were added 30ml of saturated sodium chloride aqueous solution and 20 ml of ethylacetate, followed by partitioning. The organic layer was separated andthe aqueous layer was extracted with 20 ml of ethyl acetate. Thecombined organic layer was dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation and purification by silica gelcolumn chromatography was carried out to obtain 2.39 g (yield 33%) of apale yellow, liquid compound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.18-1.32 (3H, m), 1.53-2.38 (6H,m), 2.46 (3H, s), 2.56-3.03 (2H, m), 3.18-4.59 (8H, m), 4.90-5.80 (2H,m), 6.72-6.80 (2H, m), 6.97-7.09 (1H, m), 7.30-7.39 (2H, m), 7.40-7.56(2H, m), 7.61-7.73 (3H, m), 8.21 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3450, 2940, 1740, 1600, 1510, 1270,1200, 1150, 1060, 1030, 710.

The results of elemental analysis were as follows: carbon 65.93% andhydrogen 6.13%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 16.

Example 6

Starting from the compound 16 obtained in the above Synthetic Example 3,the compound 17 of the invention was prepared.

To a solution of 2.33 g (4.01 mmol) of the compound 16 dissolved in 60 gof 1,2-dichloroethane, 20 g of isopropyl alcohol, and 20 g of glycerinwere added 0.56 ml (4.02 mmol) of triethylamine, 105 mg (0.400 mmol) oftriphenylphosphine, and 232 mg (0.201 mmol) oftetrakistriphenylphosphine palladium, followed by stirring at a bathtemperature of 100° C. for 14 hours. After cooling and concentration, 30ml of distilled water, 20 ml of saturated sodium chloride aqueoussolution, and 50 ml of ethyl acetate were added thereto, followed bypartitioning. The organic layer was separated and washed with 10 ml ofsaturated sodium chloride aqueous solution. The combined aqueous layerwas extracted with 20 ml of ethyl acetate. The combined organic layerwas dried over anhydrous magnesium sulfate. The solvent was removed bydistillation and purification by silica gel column chromatography wascarried out to obtain 744 mg (yield 44%) of a pale yellow, liquidcompound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.25 (3H, t), 1.74-1.86 (2H, m),2.21-2.40 (4H, m), 2.86-2.99 (4H, m), 3.80 (3H, s), 4.12 (2H, q), 6.13(1H, d), 6.76-6.88 (3H, m), 7.03-7.08 (1H, d), 7.45-7.54 (2H, m),7.58-7.65 (1H, m), 8.21 (2H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2940, 1740, 1670, 1650, 1510, 1270,1200, 1150, 1060, 1030, 710.

The results of elemental analysis were as follows: carbon 71.00% andhydrogen 6.43%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 17.

Example 7

Starting from the compound 17 obtained in Example 6, a mixture of thecompound 18 and the compound 19 of the invention was prepared.

To a solution of 506 mg (0.922 mmol) of the compound 17 dissolved in 5ml of ethanol was added 5 ml of 1N sodium hydroxide aqueous solution.After 1 hour of stirring, 5 ml of 1N hydrochloric acid was added toterminate the reaction. To the reaction solution was added 50 ml ofsaturated sodium chloride aqueous solution and extraction with 10 ml ofchloroform was repeated three times. The combined organic layer wasdried over anhydrous magnesium sulfate and then concentrated. Theobtained residue was purified by silica gel column chromatography toobtain 303 mg of a pale yellow, liquid compound having a mediumviscosity.

As a result of analyzing ¹H-NMR spectrum as measured indeuterochloroform, it was confirmed that the product was a mixture ofthe compound 18 and the compound 19 wherein ethanol used as the solventwas added to the double bond of the compound 18 (existing molar ratio ofthe compound 18 to the compound 19 was 45:55). Incidentally, thechemical shift value of the ethoxy group in the compound 19 was 1.13(3H, t) and 3.37-3.50 (2H, m) and the chemical shift value of CH towhich the ethoxy group was bonded was 3.68-3.83 (1H, m).

Synthetic Example 4

As starting materials for obtaining the compound of the formula (4),starting from the compound 3 and the compound 20, the compound 21 wasprepared.

A solution of 11.9 g (35.2 mmol) of the compound 3 dissolved in 100 mlof tetrahydrofuran was cooled to −78° C. with dry ice/acetone. To theresulting solution was dropwise added 26.0 ml (36.4 mmol) of 1.40 Mt-butyllithium/n-heptane solution. After the resulting mixture wasstirred at the same temperature for 10 minutes, a solution of 9.00 g(34.0 mmol) of the compound 20 dissolved in 50 ml of tetrahydrofuran wasdropwise added to the mixture. After dropwise addition, the resultingmixture was stirred at the same temperature for 5 minutes and then, thetemperature was gradually elevated. When the temperature of the reactionsolution reached −5° C., 30 ml of 10% citric acid aqueous solution wasadded to terminate the reaction. To the reaction mixture was added 60 mlof saturated sodium chloride aqueous solution, followed by partitioning.The organic layer was separated and the aqueous layer was extracted in50 ml of ethyl acetate. The combined organic layer was dried overanhydrous magnesium sulfate. The solvent was removed by distillation andpurification by silica gel column chromatography was carried out toobtain 6.03 g (yield 29%) of a pale yellow, liquid compound having amedium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.17-2.30 (24H, m), 2.45 (3H, s),2.56-2.92 (2H, m), 3.15-4.58 (8H, m), 4.95-5.83 (2H, m), 6.65-6.94 (3H,m), 7.29-7.38 (2H, m), 7.63-7.77 (2H, m).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3510, 2970, 2940, 2860, 1750, 1730,1600, 1510, 1280, 1200, 1120, 1030, 670.

The results of elemental analysis were as follows: carbon 65.51% andhydrogen 7.45%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 21.

Example 8

Starting from the compound 21 obtained in the above Synthetic Example 4,the compound 22 of the invention was prepared.

To a solution of 6.00 g (9.95 mmol) of the compound 21 dissolved in 60 gof 1,2-dichloroethane and 15 g of methanol were added 2.10 ml (15.1mmol) of triethylamine, 130 mg (0.496 mmol) of triphenylphosphine, and575 mg (0.498 mmol) of tetrakistriphenylphosphine palladium, followed bystirring at a bath temperature of 100° C. for 16 hours. After coolingand concentration, 50 ml of saturated sodium chloride aqueous solutionand 50 ml of ethyl acetate were added thereto, followed by partitioning.The organic layer was separated and washed with 10 ml of saturatedsodium chloride aqueous solution. The combined aqueous layer wasextracted with 30 ml of ethyl acetate. The combined organic layer wasdried over anhydrous magnesium sulfate. The solvent was removed bydistillation and purification by silica gel column chromatography wascarried out to obtain 936 mg (yield 21%) of a pale yellow, liquidcompound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.25 (3H, t), 1.29-1.52 (15H, m),1.57-1.68 (2H, m), 2.16-2.33 (4H, m), 2.82-2.96 (4H, m), 3.80 (3H, s),4.13 (2H, q), 6.10 (1H, d), 6.70-6.94 (4H, m).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2970, 2930, 2860, 1750, 1740, 1670,1630, 1610, 1510, 1270, 1200, 1120, 1040.

The results of elemental analysis were as follows: carbon 70.17% andhydrogen 8.80%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 22.

Example 9

Starting from the compound 22 obtained in Example 8, the compound 23 ofthe invention was prepared.

To a solution of 197 mg (0.441 mmol) of the compound 22 dissolved in 3.0ml of methanol was added 1.5 ml of 1N sodium hydroxide aqueous solution,followed by stirring. After 1 hour of stirring, 1.5 ml of 1Nhydrochloric acid was added to the reaction mixture to neutralize it.Then, 30 ml of saturated sodium chloride aqueous solution was added andextraction with 10 ml of chloroform was repeated three times. Thecombined organic layer was dried over anhydrous magnesium sulfate andthen the solvent was removed by distillation. The obtained residue waspurified by silica gel column chromatography to obtain 59.7 mg (44%) ofa pale yellow, liquid compound having a low viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.22-1.53 (8H, m), 1.57-1.70 (2H,m), 2.32-2.44 (3H, m), 2.58-2.88 (5H, m), 3.28 (3H, s), 3.60-3.69 (1H,m), 3.87 (3H, s), 5.56 (1H, br), 6.63-6.72 (2H, m), 6.78-6.85 (1H, m).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3410, 2930, 2860, 1710, 1610, 1520,1270, 1240, 1150, 1120, 1030, 820, 800.

The results of elemental analysis were as follows: carbon 78.56% andhydrogen 10.05%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 23.

Synthetic Example 5

As starting materials for obtaining the compound of the formula (4),starting from the compound 3 and the compound 24, the compound 25 wasprepared.

According to the method of Synthetic Example 1, 663 mg (yield 32%) ofthe compound 25 as a pale yellow, liquid compound having a mediumviscosity was obtained from 1.19 g (3.52 mmol) of the compound 3 and 851mg (3.40 mmol) of the compound 20.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.22-1.60 (18H, m), 1.99-2.2.45(4H, m), 2.78 (3H, s), 2.77-2.84 (2H, m), 2.94 (1H, t), 3.71-3.80 (4H,m), 4.12 (2H, q), 5.37-5.5.43 (1H, m), 5.47-5.53 (1H, m), 6.74-6.94 (3H,m), 7.30-7.35 (2H, m), 7.72-7.77 (2H, m).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3510, 2970, 2940, 2860, 1750, 1730,1600, 1510, 1280, 1200, 1120, 1030, 670.

The results of elemental analysis were as follows: carbon 65.28% andhydrogen 7.53%.

Example 10

Starting from the compound 25 obtained in Synthetic Example 5, thecompound 26 of the invention was prepared.

According to the method of Example 1, 936 mg (yield 21%) of the compound26 as a pale yellow, liquid compound having a medium viscosity wasobtained from 6 g (9.95 mmol) of the compound 25.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.73 (17H, m), 2.18-2.31 (4H,m), 2.79-2.93 (5H, m), 3.79 (3H, s), 4.12 (2H, q), 6.09 (1H, d),6.75-6.83 (3H, m), 6.91 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2979, 1760, 1732, 1668, 1603, 1512,1468, 1369, 1267, 1150, 1127, 1038.

The results of elemental analysis were as follows: carbon 69.42% andhydrogen 8.39%.

Example 11

The compound 26 obtained in Example 10 was reduced to obtain thecompound 27 of the invention.

A solution of 588 mg (1.36 mmol) of the compound 26 and 1.52 g (4.08mmol) of cerium chloride heptahydrate dissolved in 24 ml of methanol wascooled to −78° C. with dry ice/acetone. To the solution was added 77.1mg (2.04 mmol) of sodium borohydride, followed by stirring at the sametemperature for 15 minutes. To the reaction mixture were added 40 ml ofsaturated sodium chloride aqueous solution and 80 ml of ethyl acetate,followed by partitioning. The organic layer was separated and theaqueous layer was extracted with 40 ml of ethyl acetate. The combinedorganic layer was dried over anhydrous magnesium sulfate. Then, thesolvent was removed by distillation and drying under reduced pressurewas carried out to obtain 575 mg (97.3%) of a pale yellow, liquidcompound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.64 (17H, m), 1.82-1.84 (2H,m), 2.04 (2H, dd), 2.29 (2H, t), 2.64-2.70 (2H, m), 2.70-2.84 (1H, m),3.80 (3H, s), 4.07-4.15 (3H, m), 5.46-5.52 (1H, m), 5.61-5.68 (1H, m),6.75-6.79 (2H, m), 6.90 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3504, 2974, 1761, 1736, 1606, 1511,1467, 1418, 1280, 1182, 1127, 1098, 1036.

The results of elemental analysis were as follows: carbon 69.10% andhydrogen 8.81%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 27.

Example 12

The compound 27 obtained in Example 11 was epoxidized to obtain thecompound 28 of the invention.

To a solution of 257 mg (0.591 mmol) of the compound 27 dissolved in 9ml of dichloromethane was dropwise added 204 mg (1.18 mmol) ofm-chloroperbenzoic acid dissolved in 3 ml of dichloromethane under icecooling. After 4 hours of stirring at the same temperature, 10 ml of 10%sodium thiosulfate aqueous solution was added to the reaction mixtureand extraction with 10 ml of chloroform was repeated two times. Thecombined organic layer was dried over anhydrous magnesium sulfate andthen the solvent was removed by distillation. The obtained residue waspurified by silica gel thin-layer chromatography to obtain 257 mg (97%)of a pale yellow, liquid compound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.95 (21H, m), 2.29 (2H, t),2.72-2.91 (5H, m), 3.51-3.53 (1H, m), 3.80 (3H, s), 4.12 (2H, q),6.76-6.80 (2H, m), 6.92 (1H, d).

The results of elemental analysis were as follows: carbon 66.64% andhydrogen 8.50%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 28.

Example 13

The compound 22 obtained in Example 8 was catalytically hydrogenated toobtain the compound 29 of the invention.

To a solution of 1 g (2.24 mmol) of the compound 22 dissolved in 25 mlof ethanol was added 100 mg of palladium-carbon. After the reactionsystem was stirred under a hydrogen atmosphere for 3.5 hours, thereaction solution was filtrated through celite to remove the palladiumcatalyst by filtration. The filtrate was concentrated under reducedpressure to obtain 0.97 g (yield 97%) of a pale yellow, liquid compoundhaving a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.61 (24H, m), 2.28 (2H, t),2.37 (2H, t), 2.71 (1H, t), 2.87 (2H, t), 3.78 (3H, s), 4.12 (2H, q),6.72-6.77 (2H, m), 6.89 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2930, 1760, 1730, 1639, 1511, 1452,1419, 1369, 1267, 1183, 1126.

The results of elemental analysis were as follows: carbon 69.61% andhydrogen 8.99%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 29.

Example 14

The compound 26 obtained in Example 10 was catalytically hydrogenated toobtain the compound 30 of the invention.

According to the method of Example 13, 148 mg (yield 91%) of thecompound 30 as a pale yellow, liquid compound having a medium viscositywas obtained from 161 mg (0.379 mmol) of the compound 26.

The chemical shift values of the compound 30 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.23-1.71 (21H, m), 2.28(2H, t), 2.38 (2H, t), 2.43-2.45 (1H, m), 2.72 (2H, t), 2.87 (2H, t),3.79 (3H, s), 4.12 (2H, q), 6.72-6.78 (2H, m), 6.60 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2930, 1760, 1730, 1639, 1511, 1452,1419, 1369, 1267, 1183, 1126, 1098, 1029, 1015.

The results of elemental analysis were as follows: carbon 69.10% andhydrogen 8.81%.

Example 15

The compound 30 obtained in Example 14 was reduced with sodiumborohydride to obtain the compound 31 of the invention.

A solution of 188 mg (0.433 mmol) of the compound 30 dissolved in 5 mlof methanol was added 16.4 mg (0.433 mmol) of sodium borohydride underice cooling. After stirring at room temperature for 2 hours, to thereaction mixture were added 10 ml of saturated sodium chloride aqueoussolution and 10 ml of ethyl acetate, followed by partitioning. Theorganic layer was separated and the aqueous layer was extracted with 10ml of ethyl acetate. After the combined organic layer was dried overanhydrous magnesium sulfate, the solvent was removed by distillation anddrying under reduced pressure was carried out to obtain 187 mg (99%) ofa pale yellow, liquid compound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.20-1.72 (28H, m), 2.26 (2H, t),2.55-2.65 (1H, m), 2.70-2.80 (1H, m), 3.54-3.63 (1H, m), 3.76 (3H, s),4.09 (2H, q), 6.72-6.75 (2H, m), 6.86 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3466, 2933, 1739, 1600, 1513, 1465,1371, 1267, 1142, 1040.

The results of elemental analysis were as follows: carbon 68.78% andhydrogen 9.23%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 31.

Example 16

The compound 26 obtained in Example 10 was ketalized to obtain thecompound 32 of the invention.

The present reaction was carried out under a nitrogen atmosphere. To asolution of 11 μl (0.0614 mmol) of trimethylsilyltrifluoromethanesulfonate and 0.9 ml (3.69 mmol) of1,2-bistrimethylsiloxyethane dissolved in 6 ml of dichloromethane wasdropwise added a solution of 133 mg (0.307 mmol) of the compound 26dissolved in 1 ml of dichloromethane under ice cooling. After 50 minutesof stirring, triethylamine was added to the reaction mixture toterminate the reaction. Then, 5 ml of saturated sodium bicarbonateaqueous solution and 5 ml of chloroform were added, followed bypartitioning. The organic layer was separated and dried over anhydrousmagnesium sulfate and then the solvent was removed by distillation. Theobtained residue was purified by silica gel thin-layer chromatography toobtain 114 mg (78%) of a pale yellow, liquid compound having a mediumviscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.64 (17H, m), 1.98-2.06 (4H,m), 2.28 (2H, t), 2.67-2.71 (2H, m), 2.80-2.84 (1H, m), 3.79 (3H, s),3.91-3.98 (4H, m), 4.12 (2H, q), 5.38 (1H, d), 5.81 (1H, dt), 6.74-6.78(2H, m), 6.89 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2924, 1758, 1737, 1608, 1510, 1466,1420, 1127, 1042.

The results of elemental analysis were as follows: carbon 68.04% andhydrogen 8.46%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 32.

Example 17

The compound 29 obtained in Example 13 was ketalized to obtain thecompound 33 of the invention.

According to the method of Example 16, 200 mg (78%) of the compound 33as a pale yellow, liquid compound having a medium viscosity was obtainedfrom 234 mg (0.522 mmol) of the compound 29.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.35 (22H, m), 1.59-1.64 (4H,m), 1.90-1.94 (2H, m), 2.28 (2H, t), 2.64-2.68 (2H, m), 3.78 (3H, s),3.98 (4H, s), 4.12 (2H, q), 6.74-6.78 (2H, m), 6.88 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 2936, 1755, 1735, 1606, 1511, 1464,1418, 1266, 1203, 1117, 1036.

The results of elemental analysis were as follows: carbon 68.54% andhydrogen 8.63%.

Example 18

Water molecule was added to the compound 26 obtained in Example 10 andremoval of the protective group of the phenolic hydroxyl group and theprotective group of the carboxyl group was carried out to obtain thecompound 34 of the invention.

To a solution of 43 mg (99.4 μmol) of the compound 26 dissolved in 3 mlof toluene were added 2 ml of 1N sodium hydroxide aqueous solution and3.5 mg (9.9 μmol) of benzyltributylammonium bromide, followed by 18hours of stirring at room temperature. The organic layer was separatedand 1N hydrochloric acid was added to the aqueous layer to neutralizeit. The aqueous layer was extracted with 5 ml of chloroform three times.The combined organic layer was dried over anhydrous magnesium sulfateand then the solvent was removed by distillation. The obtained residuewas purified by silica gel thin-layer chromatography to obtain 23.2 mg(66%) of a yellow, liquid compound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.00-1.77 (10H, m), 2.18-2.33 (2H,m), 2.65 (2H, t), 2.88 (2H, t), 3.20-3.24 (2H, m), 3.72-3.86 (4H, m)4.75 (1H, s), 5.30 (1H, br), 6.68-6.72 (2H, m), 6.83 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3336, 2943, 1723, 1710, 1603, 1514,1426, 1275, 1212.

The results of elemental analysis were as follows: carbon 64.75% andhydrogen 8.01%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 34.

Example 19

The compound 34 obtained in Example 18 was reduced to obtain thecompound 35 of the invention.

A solution of 35.2 mg (0.103 mmol) of the compound 34 dissolved in 2 mlof methanol was added 5.8 mg (0.154 mmol) of sodium borohydride underice cooling. After stirring at a bath temperature of 60° C. for 6 hours,5 ml of saturated sodium chloride aqueous solution and 5 ml of ethylacetate were added to the reaction mixture, followed by partitioning.The organic layer was separated and the aqueous layer was extracted with5 ml of ethyl acetate three times. After the combined organic layer wasdried over anhydrous magnesium sulfate and the solvent was removed bydistillation. The obtained residue was purified by silica gel thin-layerchromatography to obtain 7.4 mg (21%) of a colorless crystallinecompound.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuteromethanol were as follows: 1.10-1.90 (12H, m), 2.18-2.33 (2H,m), 2.39-2.43 (2H, m), 2.79-2.83 (2H, m), 3.64-3.87 (4H, m), 6.65-6.68(2H, m), 6.74 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3448, 2924, 1701, 1621, 1560, 1524,1410, 1212, 1127, 1098, 1028.

The results of elemental analysis were as follows: carbon 64.38% andhydrogen 8.53%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 35.

Example 20

Methanol was added to the compound 26 obtained in Example 10 and removalof the protective group of the phenolic hydroxyl group was carried outto obtain the compound 36 of the invention.

To a solution of 432 mg (0.999 mmol) of the compound 26 dissolved in 6ml of methanol were added a solution of 80 mg (2 mmol) of sodiumhydroxide previously dissolved in 4 ml of methanol. After 4 hours ofstirring at room temperature, 1N hydrochloric acid was added to effectneutralization. After the solvent was removed by distillation, 10 ml ofsaturated sodium chloride aqueous solution was added to the obtainedresidue and the mixture was extracted with 10 ml of ethyl acetate threetimes. The combined organic layer was dried over anhydrous magnesiumsulfate and then the solvent was removed by distillation. The obtainedresidue was purified by silica gel thin-layer chromatography to obtain154 mg (41%) of a pale yellow, liquid compound having a mediumviscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.29-1.63 (10H, m), 2.30 (2H, t),2.39 (2H, dd), 2.64 (1H, dd), 2.73-2.76 (2H, m), 2.81-2.83 (2H, m), 3.25(3H, s), 3.64-3.67 (4H, m), 3.88 (3H, s), 5.51 (1H, s), 6.66-6.70 (2H,m), 6.82 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3413, 2931, 1733, 1604, 1515, 1436,1364, 1267, 1238, 1196, 1155, 1127, 1084, 1072, 1028.

The results of elemental analysis were as follows: carbon 66.29% andhydrogen 8.48%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 36.

Example 21

The compound 27 obtained in Example 11 was hydrolyzed to obtain thecompound 37 of the invention.

To a solution of 209 mg (0.480 mmol) of the compound 27 dissolved in 4ml of ethanol was added 2 ml of 1N sodium hydroxide aqueous solution,followed by stirring. After 6 hours of stirring at a bath temperature of80° C., 1N hydrochloric acid was added to effect neutralization. Afterthe reaction solution was concentrated under reduced pressure andethanol was removed by distillation, 10 ml of saturated sodium chlorideaqueous solution was added and the mixture was extracted with 10 ml ofethyl acetate three times. The combined organic layer was dried overanhydrous magnesium sulfate and then the solvent was removed bydistillation. The obtained residue was purified by silica gel thin-layerchromatography to obtain 100 mg (62%) of a pale yellow, liquid compoundhaving a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.12-2.35 (14H, m), 2.60-2.90 (2H,m), 3.86 (3H, s), 4.07-4.13 (1H, m), 5.36-5.53 (1H, m), 5.59-5.67 (1H,m), 6.64-6.70 (2H, m), 6.81 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3403, 2926, 2858, 2368, 1700, 1515,1417, 1274, 1034.

The results of elemental analysis were as follows: carbon 67.83% andhydrogen 8.39%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 37.

Example 22

The compound 30 obtained in Example 14 was hydrolyzed to obtain thecompound 38 of the invention.

According to the method of Example 21, 136 mg (89%) of the compound 38as a colorless crystalline compound was obtained from 199 mg (0.457mmol) of the compound 30.

The chemical shift values of the compound 38 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.11-1.64 (12H, m),2.32-2.38 (4H, m), 2.69 (2H, t), 2.82 (2H, t), 3.87 (3H, s), 5.55 (1H,br), 6.65-6.69 (2H, m), 6.81 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3414, 2935, 1703, 1611, 1520, 1466,1409, 1279, 1228, 1122, 1028.

The results of elemental analysis were as follows: carbon 67.83% andhydrogen 8.39%.

Example 23

The compound 31 obtained in Example 15 was hydrolyzed to obtain thecompound 39 of the invention.

According to the method of Example 21, 134 mg (91%) of the compound 39as a colorless crystalline compound was obtained from 187 mg (0.433mmol) of the compound 31.

The chemical shift values of the compound 39 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.23-1.77 (16H, m), 2.33(2H, t), 2.56-2.63 (1H, m), 2.68-2.74 (1H, m), 3.59-3.66 (1H, m), 3.87(3H, s), 5.50 (1H, br), 6.67-6.70 (2H, m), 6.82 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3413, 2931, 1705, 1612, 1515, 1435,1367, 1264, 1154, 1038.

The results of elemental analysis were as follows: carbon 67.43% andhydrogen 8.93%.

Example 24

The compound 22 obtained in Example 8 was reduced with lithium aluminumhydride to obtain the compound 40 of the invention.

To a solution of 594 mg (1.33 mmol) of the compound 22 dissolved in 40ml of tetrahydrofuran was added 202 mg (5.32 mmol) of lithium aluminumhydride. After 1 hour of stirring at room temperature, 1N hydrochloricacid was added to the reaction mixture to terminate the reaction. Then,15 ml of distilled water was added and extraction with 20 ml of ethylacetate was repeated twice. The combined organic layer was dried overanhydrous magnesium sulfate and then the solvent was removed bydistillation. The obtained residue was purified by silica gel columnchromatography to obtain 315 mg (73%) of a colorless, liquid compoundhaving a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.23-1.83 (12H, m), 2.02 (2H, m),2.56-2.69 (2H, m), 3.61 (2H, t), 3.84 (3H, s), 4.04 (1H, dd), 5.45-5.49(1H, m), 5.58-5.66 (1H, m), 6.65-6.67 (2H, m), 6.79 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3349, 2930, 1666, 1602, 1516, 1464,1453, 1431, 1368, 1273, 1236, 1154, 1036.

The results of elemental analysis were as follows: carbon 70.77% andhydrogen 9.38%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 40.

Example 25

The compound 40 obtained in Example 24 was epoxidized to obtain thecompound 41 of the invention.

To a solution of 87.3 mg (0.271 mmol) of the compound 40 dissolved in 5ml of dichloromethane was dropwise added 93.6 mg (0.542 mmol) ofm-chloroperbenzoic acid dissolved in 3 ml of dichloromethane under icecooling. After 6.5 hours of stirring at the same time, 5 ml of 10%sodium thiosulfate aqueous solution was added to the reaction mixtureand extraction with 5 ml of chloroform was repeated two times. Thecombined organic layer was dried over anhydrous magnesium sulfate andthen the solvent was removed by distillation. The obtained residue waspurified by silica gel thin-layer chromatography to obtain 44.6 mg (49%)of a pale yellow, liquid compound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.33-2.30 (15H, m), 2.64-3.10 (4H,m), 3.62 (2H, t), 3.80-3.87 (4H, m), 6.68-6.71 (2H, m), 6.82 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3394, 2931, 1723, 1603, 1517, 1453,1430, 1368, 1270, 1035.

The results of elemental analysis were as follows: carbon 67.83% andhydrogen 8.39%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 41.

Example 26

The compound 30 obtained in Example 14 was reduced with lithium aluminumhydride to obtain the compound 42 of the invention.

According to the method of Example 24, 97.4 mg (91%) of the compound 42as a colorless crystalline compound was obtained from 148 mg (0.330mmol) of the compound 30.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.26-1.72 (18H, m), 2.54-2.61 (1H,m), 2.66-2.70 (1H, m), 3.54-3.73 (3H, m), 3.85 (3H, s), 6.66-6.68 (2H,m), 6.80 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3426, 2930, 1607, 1515, 1481, 1468,1437, 1365, 1268, 1239, 1155, 1124, 1039.

The results of elemental analysis were as follows: carbon 70.33% andhydrogen 9.94%.

Example 27

The compound 32 obtained in Example 16 was reduced with lithium aluminumhydride to obtain the compound 43 of the invention.

To a solution of 159 mg (0.334 mmol) of the compound 32 dissolved in 6ml of tetrahydrofuran was added 50.0 mg (1.33 mmol) of lithium aluminumhydride under ice cooling. After 1 hour of stirring at room temperature,1N hydrochloric acid was added to the reaction mixture to terminate thereaction. Then, 5 ml of saturated sodium chloride aqueous solution wasadded and extraction with 5 ml of ethyl acetate was repeated threetimes. The combined organic layer was dried over anhydrous magnesiumsulfate and then the solvent was removed by distillation. The obtainedresidue was purified by silica gel thin-layer chromatography to obtain121 mg (99%) of a yellow, liquid compound having a medium viscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.26-1.55 (10H, m), 1.96-2.06 (4H,m), 2.62-2.66 (2H, m), 3.62 (2H, t), 3.86 (3H, s), 3.91-3.99 (4H, m),5.38 (1H, d), 5.61 (1H, s), 5.81 (1H, dt), 6.66-6.69 (2H, m), 6.82 (1H,d).

The results of elemental analysis were as follows: carbon 69.20% andhydrogen 8.85%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 43.

Example 28

The compound 33 obtained in Example 17 was reduced with lithium aluminumhydride to obtain the compound 44 of the invention.

According to the method of Example 27, 137 mg (99%) of the compound 44as a yellow, liquid compound having a medium viscosity was obtained from186 mg (0.378 mmol) of the compound 33.

The chemical shift values of the compound 44 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.24-1.70 (16H, m),1.88-1.93 (2H, m), 2.59-2.63 (2H, m), 3.64 (2H, t), 3.87 (3H, s), 3.98(4H, s), 5.50 (1H, br), 6.67-6.70 (2H, m), 6.82 (1H, d).

The results of elemental analysis were as follows: carbon 69.20% andhydrogen 8.85%.

Example 29

The ketal of the compound 43 obtained in Example 27 was removed toobtain the compound 45 of the invention.

To a solution of 122 mg (0.335 mmol) of the compound 43 dissolved in 2ml of acetone and 2 ml of distilled water was added 8.4 mg (0.0335 mmol)of pyridinium p-toluenesulfonate. The reaction solution was heated underreflux over a period of 3 hours. After the reaction solution was allowedto cool to room temperature, the solvent was removed by distillation. Tothe obtained residue was added 5 ml of saturated sodium chloride aqueoussolution, and extraction with 5 ml of ethyl acetate was repeated threetimes. The combined organic layer was dried over anhydrous magnesiumsulfate and then the solvent was removed by distillation. The obtainedresidue was purified by silica gel thin-layer chromatography to obtain85.2 mg (80%) of a pale yellow, liquid compound having a mediumviscosity.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.30-1.58 (10H, m), 2.17 (2H, dd),2.81-2.86 (4H, m), 3.63 (2H, t), 3.86 (3H, s), 5.73 (1H, s), 6.08 (1H,dt), 6.67-6.71 (2H, m), 6.78-6.83 (2H, m).

The results of elemental analysis were as follows: carbon 71.22% andhydrogen 8.81%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 45.

Example 30

The ketal of the compound 44 obtained in Example 28 was removed toobtain the compound 46 of the invention.

According to the method of Example 29, 120 mg (99%) of the compound 46as a colorless crystalline compound was obtained from 137 mg (0.377mmol) of the compound 44.

The chemical shift values of the compound 46 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.20-1.51 (14H, m), 2.29(2H, t), 2.62 (2H, t), 2.75 (2H, t), 3.59 (2H, t), 3.81 (3H, s), 5.47(1H, s), 6.64-6.67 (2H, m), 6.80 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3415, 2920, 1705, 1611, 1520, 1463,1455, 1365, 1278, 1236, 1151, 1122, 1064, 1028.

The results of elemental analysis were as follows: carbon 70.77% andhydrogen 9.38%.

Example 31

The compound 28 obtained in Example 12 was reduced to obtain thecompound 47 of the invention.

To a solution of 117 mg (0.260 mmol) of the compound 28 dissolved in 10ml of tetrahydrofuran was added 59.1 mg (1.56 mmol) of lithium aluminumhydride under ice cooling. After 1 hour of stirring at room temperature,1N hydrochloric acid was added to the reaction mixture to terminate thereaction. Then, 5 ml of saturated sodium chloride aqueous solution wasadded and extraction with 10 ml of ethyl acetate was repeated threetimes. The combined organic layer was dried over anhydrous magnesiumsulfate and then the solvent was removed by distillation. The obtainedresidue was purified by silica gel thin-layer chromatography to obtain81.4 mg (92%) of a colorless crystalline compound.

The chemical shift values of the product on ¹H-NMR spectrum as measuredin deuterochloroform were as follows: 1.24-1.78 (16H, m), 3.63-3.70 (3H,m), 3.88-3.96 (4H, m), 5.49 (1H, s), 6.69-6.73 (2H, m), 6.84 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3416, 2930, 1653, 1609, 1516, 1453,1429, 1368, 1274, 1239, 1154, 1030.

The results of elemental analysis were as follows: carbon 67.03% andhydrogen 9.47%.

Based on the above analysis, it was confirmed that the obtained compoundwas the compound 47.

Example 32

The compound 36 obtained in Example 20 was reduced with lithium aluminumhydride to obtain the compound 48 of the invention.

According to the method of Example 24, 97.1 mg (68%) of the compound 48as a colorless, liquid compound having a medium viscosity was obtainedfrom 154 mg (0.405 mmol) of the compound 36.

The chemical shift values of the compound 48 on ¹H-NMR spectrum asmeasured in deuterochloroform were as follows: 1.26-1.80 (14H, m),2.58-2.2.64 (1H, m), 2.68-2.74 (1H, m), 3.35-3.63 (4H, m), 3.61 (2H, t),3.79-3.89 (4H, m), 5.78 (1H, s), 6.67-6.73 (2H, m), 6.81 (1H, d).

The wave numbers (cm⁻¹) with absorption on IR absorption spectrum (KBrpellet method) were as follows: 3389, 2932, 2857, 1602, 1516, 1453,1428, 1371, 1272, 1238, 1084, 1036.

The results of elemental analysis were as follows: carbon 68.15% andhydrogen 9.15%.

Test Example 1

Using the compound 7 obtained in Example 2, the compound 13 obtained inExample 5, a mixture of the compound 18 and the compound 19 (existingmolar ratio 45:55) obtained in Example 7, and arbutin (manufactured byTokyo Kasei Kogyo Co., Ltd.) as a comparative control, a tyrosinaseactivity inhibition test was carried out using L-dopa as a substrate.

The specific test procedures are as follows.

(1) 1.80 ml of a phosphate buffer prepared by dissolving 1.000 g ofsodium dihydrogen phosphate and 1.186 g of disodium hydrogen phosphatein 500 ml of distilled water, 1.00 ml of a substrate solution preparedby dissolving 32.7 mg of L-DOPA in 200 ml of distilled water, and 0.10ml of a test solution prepared by dissolving the test compound indimethyl sulfoxide were mixed together.

(2) 0.10 ml of an enzyme solution prepared by dissolving 3.0 mg (2400units; manufactured by Sigma Corporation) of mushroom tyrosinase in 7.0ml of distilled water was added to the solution prepared in (1), and thewhole was stirred for 15 seconds. The resulting solution was maintainedat 25° C., and the absorbance at 475 nm was measured one minute and 45seconds later and 2 minutes and 45 seconds later.

(3) The test operations in the above (1) and (2) were conducted threetimes for the individual test compounds and blank test (only dimethylsulfoxide), and the resulting numeric value was inserted in thefollowing calculation formula and a mean value thereof was regarded as atyrosinase activity inhibition ratio (%).Tyrosinase activity inhibition ratio (%)=[(T ¹ −T ²)/T ¹]×100T¹=difference in absorbance of solution with addition of no testcompound between 2 minutes and 45 seconds later and one minute and 45seconds laterT²=difference in absorbance of solution with addition of test compoundwas added between 2 minutes and 45 seconds later and one minute and 45seconds later

Table 1 shows the results in the case that the compounds of theinvention and arbutin were individually used in the enzymatic reactionsolution in amounts of 0.5 mg/ml and 1 mg/ml. TABLE 1 Tyrosinaseactivity inhibition ratio (%) 0.5 mg/mL 1 mg/mL Compound 7 59.8 77.1Compound 13 58.5 76.5 Mixture of Compounds 47.5 71.7 18 and 19 Arbutin36.2 42.2

As a result of the test, it was found that the compounds of theinvention each had an effect superior to that of arbutin as a knowntyrosinase activity inhibitor.

Test Example 2

Using the compound 40 obtained in Example 24 and arbutin (manufacturedby Tokyo Kasei Kogyo Co., Ltd.) as a comparative control, a tyrosinaseactivity inhibition test was carried out using L-dopa as a substrate.The test procedure was in accordance with Test Example 1.

Table 2 shows the results in the case that the compounds of theinvention and arbutin were individually used in the enzymatic reactionsolution in amounts of 0.125 mg/ml, 0.250 mg/ml, and 0.50 mg/ml. TABLE 2Tyrosinase activity inhibition ratio (%) Test compound 0.5 mg/mL 0.25mg/mL 0.125 mg/mL Compound 40 45.3 36.5 25.5 Arbutin 34.6 28.5 23.1

As a result of the test, it was found that the compound 40 of theinvention had an effect superior to that of arbutin as a knowntyrosinase activity inhibitor.

Test Example 3

Using the compound 37 obtained in Example 21, the compound 38 obtainedin Example 22, the compound 39 obtained in Example 23, and arbutin(manufactured by Tokyo Kasei Kogyo Co., Ltd.) as a comparative control,a tyrosinase activity inhibition test was carried out using L-dopa as asubstrate.

The specific test procedures are as follows.

(1) 72 μl of a phosphate buffer prepared by dissolving 1.000 g of sodiumdihydrogen phosphate and 1.186 g of disodium hydrogen phosphate in 500ml of distilled water, 80 μl of a substrate solution prepared bydissolving 32.7 mg of L-DOPA in 200 ml of distilled water, and 8 μl of atest solution prepared by dissolving the test compound in dimethylsulfoxide were mixed together.

(2) 80 μl of an enzyme solution prepared by dissolving 3.0 mg (2400units; manufactured by Sigma Corporation) of mushroom tyrosinase in 7.0ml of distilled water and diluting the solution with the above phosphatebuffer so as to make it five times in amount was added to the solutionprepared in (1), and the whole was stirred for 15 seconds. The resultingsolution was maintained at 25° C., and the absorbance at 490 nm wasmeasured by a microplate reader one minute and 45 seconds later and 2minutes and 45 seconds later.

(3) The test operations in the above (1) and (2) were conducted fourtimes for the individual test compounds and blank test (only dimethylsulfoxide), and the resulting numeric value was inserted in thefollowing calculation formula and a mean value thereof was regarded as atyrosinase activity inhibition ratio (%).Tyrosinase activity inhibition ratio (%)=[(T ¹ −T ²)/T ¹]×100T¹=difference in absorbance of solution with addition of no testcompound between 2 minutes and 45 seconds later and one minute and 45seconds laterT²=difference in absorbance of solution with addition of test compoundwas added between 2 minutes and 45 seconds later and one minute and 45seconds later

Table 3 shows the results in the case that the compounds of theinvention and arbutin were individually used in the enzymatic reactionsolution in amounts of 0.5 mg/ml and 1.00 mg/ml. TABLE 3 Tyrosinaseactivity inhibition ratio (%) Test compound 1 mg/mL 0.5 mg/mL Compound37 67.7 48.6 Compound 38 73.3 49.9 Compound 39 75.2 51.3 Arbutin 41.635.0

As a result of the test, it was found that the compounds 37, 38, and 39of the invention each had an effect superior to that of arbutin as aknown tyrosinase activity inhibitor.

Test Example 4

Using the compound 42 obtained in Example 26, the compound 45 obtainedin Example 29, the compound 46 obtained in Example 30, and arbutin(manufactured by Tokyo Kasei Kogyo Co., Ltd.) as a comparative control,a tyrosinase activity inhibition test was carried out using L-dopa as asubstrate. The test procedure was in accordance with Test Example 3.

Table 4 shows the results in the case that the compounds of theinvention and arbutin were individually used in the enzymatic reactionsolution in amounts of 0.031 mg/ml, 0.062 mg/ml, and 0.125 mg/ml. TABLE4 Tyrosinase activity inhibition ratio (%) Test compound 0.125 mg/mL0.063 mg/mL 0.031 mg/mL Compound 42 40.6 31.3 20.1 Compound 45 27.6 18.210.7 Compound 46 36.9 23.8 14.9 Arbutin 24.7 17.7 10.7

As a result of the test, it was found that the compounds 42, 45, and 46of the invention had effects superior to that of arbutin as a knowntyrosinase activity inhibitor.

Test Example 5

Using the compound 34 obtained in Example 18, the compound 47 obtainedin Example 31, and arbutin (manufactured by Tokyo Kasei Kogyo Co., Ltd.)as a comparative control, a tyrosinase activity inhibition test wascarried out using L-dopa as a substrate. The test procedure was inaccordance with Test Example 3.

Table 5 shows the results in the case that the compounds of theinvention and arbutin were individually used in the enzymatic reactionsolution in an amount of 1.00 mg/ml. TABLE 5 Tyrosinase activity Testcompound inhibition ratio (%) Compound 34 60.1 Compound 47 57.5 Arbutin45.6

As a result of the test, it was found that the compounds 34 and 47 ofthe invention each had an effect superior to that of arbutin as a knowntyrosinase activity inhibitor.

Test Example 6

Using the compound 48 obtained in Example 32 and arbutin (manufacturedby Tokyo Kasei Kogyo Co., Ltd.) as a comparative control, a tyrosinaseactivity inhibition test was carried out using L-dopa as a substrate.The test procedure was in accordance with Test Example 3.

Table 6 shows the results in the case that the compound of the inventionand arbutin were individually used in the enzymatic reaction solution inamounts of 0.25 mg/ml and 0.50 mg/ml. TABLE 6 Tyrosinase activity Testinhibition ratio (%) compound 0.5 mg/mL 0.25 mg/mL Compound 48 47.1 38.2Arbutin 42.6 35.8

As a result of the test, it was found that the compound 48 of theinvention had an effect superior to that of arbutin as a knowntyrosinase activity inhibitor.

Test Example 7

Using the compound 7 obtained in Example 2, the compound 34, andmagnesium ascorbate phosphate as a comparative control, a hyaluronicacid-degrading enzyme activity inhibition test was carried out.

Specific test procedure was as follows.

First, the following solutions shown in A to H were each prepared.

A: 0.1M acetate buffer solution was prepared by dissolving 0.60 g ofacetic acid in 100 ml of distilled water.

B: A hyaluronidase solution was prepared by dissolving 7.2 mg of ahyaluronic acid-degrading enzyme (derived from bovine testiclesmanufactured by Sigma Corporation, Type IV-S) into 3.0 ml of the acetatebuffer (prepared in the above A).

C: An activator solution was prepared by dissolving 1.0 mg of compound48/80 (a hyaluronidase activator manufactured by Sigma Corporation) into10.0 ml of the acetate buffer (prepared in the above A).

D: A hyaluronic acid solution was prepared by dissolving 12.0 mg ofpotassium hyaluronate (manufactured by Wako Pure Chemical Industries,Ltd.) into 15.0 ml of the acetate buffer (prepared in the above A).

E: A 0.4N sodium hydroxide aqueous solution was prepared by dissolving1.60 g of sodium hydroxide into 100 ml of distilled water.

F: After 4.95 g of boric acid was dissolved into 50 ml of distilledwater, a 1N sodium hydroxide aqueous solution was added until pH reached9.1. Subsequently, the whole amount was made 100 ml by adding distilledwater.

G: 1.0 g of p-dimethylaminobenzaldehyde, 1.25 ml of 10N hydrochloricacid, and 8.75 ml of acetic acid were mixed. The solution was used afterthe whole amount was made 100 ml by adding acetic acid immediatelybefore use.

H: Each test compound was dissolved in the acetate buffer (prepared inthe above A) so the final test concentration became 0.5 mg/ml and 1.0mg/ml.

Next, the experimental operation was carried out with the proceduresshown in the following (1) to (8).

(1) 0.2 ml of the test compound solution (prepared in the above H) and0.1 ml of the hyaluronic acid-degrading enzyme solution (prepared in theB) were mixed and the whole was incubated at 37° C. for 20 minutes.

(2) To the above reaction solution was added 0.2 ml of the activatorsolution (prepared in the above C) and the whole was incubated at 37° C.for 20 minutes.

(3) To the above reaction solution was added 0.5 ml of the hyaluronicacid solution (prepared in the above D), and the whole was incubated at37° C. for 40 minutes.

(4) To the above reaction solution was added 0.2 ml of the 0.4N sodiumhydroxide aqueous solution (prepared in the above E), and the whole wascooled in an ice bath.

(5) To the above reaction solution was added 0.2 ml of the boric acidsolution (prepared in the above F), and the whole was heated at 100° C.for 3 minutes.

(6) The above reaction solution was cooled in an ice bath.

(7) To the above reaction solution was added 3.0 ml of thep-dimethylaminobenzaldehyde solution (prepared in the above G), and thewhole was incubated at 37° C. for 20 minutes.

(8) Absorbance of the reaction solution at 585 nm was measured using aspectrophotometer.

The above experimental operations were repeated three times, and theresulting numeric value was inserted in the following calculationformula and a mean value thereof was regarded as a hyaluronicacid-degrading enzyme activity inhibition ratio (%).Hyaluronic acid-degrading enzyme activity inhibition ratio(%)=(A−B)/A−100

A=absorbance obtained at the time when operation was carried out withaddition of no test compound

B=absorbance obtained at the time when operation was carried out withaddition of test compound

The compounds of the invention and magnesium ascorbate phosphate wereeach used in an enzymatic reaction solution in amounts of 0.1 mg/ml, 0.2mg/ml, and 0.4 mg/ml, and the results were shown in Table 7 (since thecompound 7 was not dissolved in a concentration of 0.4 mg/ml, the testwas not carried out). TABLE 7 Hyaluronic acid-degrading enzyme activityinhibition ratio (%) 0.1 mg/mL 0.2 mg/mL 0.4 mg/mL Compound 7 10.6 41.3— Compound 34 12.1 31.6 81.3 Magnesium 3.3 4.2 7.6 ascorbate phosphate

As a result, it was found that the compounds of the invention each hadan inhibitory effect of hyaluronic acid-degrading enzyme activity.

Test Example 8

Using the compound 7 obtained in Example 2 as well as dl-α-tocopherol(manufactured by Tokyo Kasei Kogyo Co., Ltd.) and butylhydroxytoluene(BHT) as comparative controls, a test of scavenging DDPH(1,1-diphenyl-2-picrylhydrazyl) radical, a stable radical, was carriedout.

Specific test procedure is as follows.

1 ml of 200 μM DPPH ethanol solution was added to 800 μl of 100 mMTris-HCl buffer (pH 7.4) and 200 μl of an ethanol solution of thecompound 7 (a final concentration of 10 μg/mL), followed by sufficientstirring. After the resulting mixture was allowed to stand in a darkplace at room temperature for 20 minutes, the absorbance at 517 nm wasmeasured (absorbance of the test solution)

The compound 13 of the invention as well as dl-α-tocopherol andbutylhydroxytoluene as a known radical scavenger were similarly tested.

As a control, 800 μl of 100 mM Tris-HCl buffer (pH 7.4), 200 μl ofethanol, and 1 ml of 200 μM DPPH ethanol solution were used in the samemanner as described above and the absorbance was measured (absorbance ofthe control solution).

With the individual compounds, the same measurement was repeated threetimes, and the mean value was inserted in the following formula tocalculate a DPPH radical-scavenging ratio (%) The results are shown inTable 8.DPPH radical-scavenging ratio (%)=[1−(absorbance of samplesolution/absorbance of control solution)]×100 TABLE 8 DPPHradical-scavenging ratio (%) Compound 7 33.7 Compound 13 39.0 Tocopherol28.4 BHT 63.7

It was found that, although inferior to BHT, the compounds of theinvention each had a radical-scavenging activity equal to or higher thanthat of dl-α-tocopherol. Therefore, it is judged that the compounds ofthe invention can be used as scavengers of active oxygen, particularlyhydroxy radicals.

Test Example 9

Using the compound 36 obtained in Example 20, the compound 37 obtainedin Example 21, the compound 38 obtained in Example 22, the compound 39obtained in Example 23, the compound 40 obtained in Example 24, thecompound 42 obtained in Example 26, the compound 45 obtained in Example29, the compound 46 obtained in Example 30, the compound 48 obtained inExample 32 and, as a comparative control, dl-α-tocopherol (manufacturedby Tokyo Kasei Kogyo Co., Ltd.), a test of scavenging DDPH(1,1-diphenyl-2-picrylhydrazyl) radical, a stable radical, was carriedout.

Specific test procedure is as follows.

100 μl of 800 μM DPPH ethanol solution was added to 80 μl of 100 mMTris-HCl buffer (pH 7.4) and 20 μl of an ethanol solution of thecompound 36 (final concentration of 25 μg/mL), followed by sufficientstirring. After the resulting mixture was allowed to stand in a darkplace at room temperature for 20 minutes, the absorbance at 540 nm wasmeasured on a microplate reader (absorbance of the test solution).

The compounds 37, 38, 39, 40, 42, 45, 46, 46, and 48 of the invention aswell as dl-α-tocopherol as a known radical scavenger were similarlytested.

As a control, using 80 μl of 100 mM Tris-HCl buffer (pH 7.4), 20 μl ofethanol, and 100 μl of 800 μM DPPH ethanol solution, the same operationwas carried out as described above and the absorbance was measured(absorbance of the control solution).

With the individual compounds, the same measurement was repeated fourtimes, and the mean value was inserted in the following formula tocalculate a DPPH radical-scavenging ratio. The results are shown inTable 9.DPPH radical-scavenging ratio (%)=[1−(absorbance of samplesolution/absorbance of control solution)]×100 TABLE 9 DPPHradical-scavenging ratio (%) Compound 36 31.7 Compound 37 37.6 Compound38 32.5 Compound 39 33.8 Compound 40 33.9 Compound 42 40.7 Compound 4538.4 Compound 46 39.4 Compound 48 33.5 Tocopherol 14.9

It was found that the compounds of the invention each had aradical-scavenging activity higher than that of dl-α-tocopherol.Therefore, it is judged that the compounds of the invention can be usedas scavengers of active oxygen, particularly hydroxy radicals.

Test Example 10

Using the compound 7 obtained in Example 2, the compound 38 obtained inExample 22, the compound 40 obtained in Example 24, the compound 42obtained in Example 26, the compound 46 obtained in Example 30, and as acomparative control, dl-α-tocopherol (manufactured by Tokyo Kasei KogyoCo., Ltd.), a test of suppressing lipid peroxide formation was carriedout using linoleic acid.

Specific test procedure is as follows.

(1) After ethanol (2.0 g) was added to linoleic acid (0.2 g,manufactured by Tokyo Kasei Kogyo Co., Ltd.), the compound 7 (0.01 g),and a surfactant Nissan OT-221 (0.4 g, manufactured by NOF Corporation)placed in a 50-ml screw vial and they was dissolved one another,distilled water (17.39 g) was added to the resulting solution and thewhole was stirred. Then, the whole was tightly sealed and allowed tostand in a constant-temperature chamber at 40° C. Such sample wasprepared in a duplex manner.

The same operation was carried out on the compounds 38, 40, 42, 46,dl-α-tocopherol, and a sample with addition of no test compound (blank).

(2) The amount of remaining linoleic acid after one week, 2 weeks, 3weeks, and 4 weeks from the start of the test was quantitativelydetermined by HPLC.

The HPLC analytical conditions were as follows: Wavelength fordetection: 210 nm; Mobile phase: a mixed solution of a Mc Ilvaine bufferadjusted to pH 2.6 and methanol (10:90); Flow rate: 1 ml/min; Column:ODS-80Ts (4.6 φmm×150 mm); and Column temperature: 40° C.

(3) Quantitative determination by HPLC was carried out on each sampleone time. The ratio of remaining linoleic acid was calculated on thebasis of the mean value of values obtained in two-times measurement. Theresults are shown in Table 10. TABLE 10 Ratio of remaining linoleic acid(%) After After After After 1 week 2 weeks 3 weeks 4 weeks Blank 81.360.6 40.6 19.1 Compound 7 99.3 95.1 82.0 63.4 Compound 38 99.7 95.5 83.974.8 Compound 40 99.9 97.5 86.2 75.5 Compound 42 99.3 95.4 83.3 74.1Compound 46 98.8 94.6 90.5 74.0 Tocopherol 88.7 81.3 69.7 50.0

As a result of the test, it was found that the compounds 7, 38, 40, 42,and 46 of the invention each had an effect higher than that ofdl-α-tocopherol, an existing lipid peroxide formation-suppressing agent.

INDUSTRIAL APPLICABILITY

The compounds of the present invention can be industrially produced andthey exhibit characteristics of having inhibitory activity such asexcellent tyrosinase activity inhibitory effect, hyaluronicacid-degrading enzyme, hydroxy radical-scavenging action, and lipidperoxide formation-suppressing action. Accordingly, it is possible forthe compounds of the invention to apply to the fields of foods,medicines, quasi-drugs, cosmetics, etc. As specific examples, thecompounds can be used in applications for preventing spots, freckles,aging of skin, allergy, and the like.

1. A compound represented by the following formula (1):

(wherein R¹ is a hydrogen atom, a lower alkyl group, or a protectivegroup of a phenolic hydroxyl group, R² is a hydrogen atom or aprotective group of a phenolic hydroxyl group, A is an alkylene grouphaving 1 to 4 carbon atoms, B is an alkylene group having 1 to 12 carbonatoms, R³ is —COOR⁴ (wherein R⁴ is a protective group of a carboxylgroup), a carboxyl group, or —CH₂OH, and Z is —CO—CH═CH—, —CHOH—CH═CH—,—CHOH-1,2-epoxy-, —CO—CH₂CH₂—, —CHOH—CH₂CH₂—, —CO—CH₂CHOH—,—CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—, —CHOH—CH₂CHOR⁵—, a ketal derivative of—CO—CH═CH—, or a ketal derivative of —CO—CH₂CH₂— and R⁵ is a lower alkylgroup when R³ is a —COOR⁴ group, Z is —CO—CH═CH—, —CHOH—CH═CH—,—CHOH-1,2-epoxy-, —CHOH—CH₂CH₂—, —CHOH—CH₂CHOH—, —CO—CH₂CHOR⁵—,—CHOH—CH₂CHOR⁵—, a ketal derivative of —CO—CH═CH—, or a ketal derivativeof —CO—CH₂CH₂— and R⁵ is a lower alkyl group when R³ is a carboxylgroup, or Z is —CHOH—CH═CH—, —CHOH-1,2-epoxy-, —CHOH—CH₂CHOH—,—CO—CH₂CHOR⁵—, —CHOH—CH₂CHOR⁵—, a ketal derivative of —CO—CH═CH—, or aketal derivative of —CO—CH₂CH₂— and R⁵ is a lower alkyl group when R³ isa —CH₂OH).
 2. A tyrosinase inhibitor comprising the compound representedby the formula (1) according to claim
 1. 3. A hyaluronic acid-degradingenzyme inhibitor comprising the compound represented by the formula (1)according to claim
 1. 4. An antioxidant comprising the compoundrepresented by the formula (1) according to claim
 1. 5. A tyrosinaseinhibitor containing a compound represented by the following formula(2):

(wherein R⁶ is a hydrogen atom, a lower alkyl group, or a protectivegroup of a phenolic hydroxyl group, A is an alkylene group having 1 to 4carbon atoms, B is an alkylene group having 1 to 12 carbon atoms, R⁷ is—COOR⁸ (wherein R⁸ is a protective group of a carboxyl group), acarboxyl group, or —CH₂OH, Z is —CO—CH═CH—, —CHOH—CH═CH—,—CHOH-1,2-epoxy-, —CO—CH₂CH₂—, —CHOH—CH₂CH₂—, —CO—CH₂CHOH—,—CHOH—CH₂CHOH—, —CO—CH₂CHOR⁹—, —CHOH—CH₂CHOR⁹—, a ketal derivative of—CO—CH═CH—, or a ketal derivative of —CO—CH₂CH₂—, and R⁹ is a loweralkyl group).
 6. A hyaluronic acid-degrading enzyme inhibitor comprisingthe compound represented by the above formula (2).
 7. An antioxidantcomprising the compound represented by the above formula (2).